common presentation of lung cancer

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Lung cancer

• Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for the highest mortality rates among both men and women.
• Smoking is the leading cause of lung cancer, responsible for approximately 85% of all cases.
• Lung cancer is often diagnosed at advanced stages when treatment options are limited.
• Screening high risk individuals has the potential to allow early detection and to dramatically improve survival rates.
• Primary prevention (such as tobacco control measures and reducing exposure to environmental risk factors) can reduce the incidence of lung cancer and save lives.

Lung cancer is a type of cancer that starts when abnormal cells grow in an uncontrolled way in the lungs. It is a serious health issue that can cause severe harm and death.

Symptoms of lung cancer include a cough that does not go away, chest pain and shortness of breath.

It is important to seek medical care early to avoid serious health effects. Treatments depend on the person’s medical history and the stage of the disease.

The most common types of lung cancer are non-small cell carcinoma (NSCLC) and small cell carcinoma (SCLC). NSCLC is more common and grows slowly, while SCLC is less common but often grows quickly.

Lung cancer is a significant public health concern, causing a considerable number of deaths globally. GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer (IARC) show as lung cancer remains the leading cause of cancer death, with an estimated 1.8 million deaths (18%) in 2020.

Smoking tobacco (including cigarettes, cigars, and pipes) is the primary risk factor for lung cancer but it can also affect non-smokers. Other risk factors include exposure to secondhand smoke, occupational hazards (such as asbestos, radon and certain chemicals), air pollution, hereditary cancer syndromes, and previous chronic lung diseases.

Lung cancer can cause several symptoms that may indicate a problem in the lungs.

The most common symptoms include:

• cough that does not go away
• shortness of breath
• coughing up blood (haemoptysis)
• weight loss with no known cause
• lung infections that keep coming back.

Early symptoms may be mild or dismissed as common respiratory issues, leading to delayed diagnosis.

Not smoking tobacco is the best way to prevent lung cancer.

Other risk factors to avoid include:

• secondhand smoke
• air pollution
• workplace hazards like chemicals and asbestos.

Early treatment can prevent lung cancer from becoming worse and spreading to other parts of the body.

Prevention of lung cancer include primary and secondary prevention measures. Primary prevention aims to prevent the initial occurrence of a disease through risk reduction and promoting healthy behaviour. In public health, these preventive measures include smoking cessation, promoting smoke-free environments, implementing tobacco control policies, addressing occupational hazards, and reducing air pollution levels.

Secondary prevention for lung cancer involves screening methods that aim to detect the disease in its early stages, before symptoms become apparent and can be indicated for high-risk individuals. In this population, early detection can significantly increase the chances of successful treatment and improve outcomes. The primary screening method for lung cancer is low-dose computed tomography (LDCT).

Diagnostic methods for lung cancer include physical examination, imaging (such as chest X-rays, computed tomography scans, and magnetic resonance imaging), examination of the inside of the lung using a bronchoscopy, taking a sample of tissue (biopsy) for histopathology examination and definition of the specific subtype (NSCLC versus SCLC), and molecular testing to identify specific genetic mutations or biomarkers to guide the best treatment option.

Treatment and care

Treatments for lung cancer are based on the type of cancer, how much it has spread, and the person’s medical history. Early detection of lung cancer can lead to better treatments and outcomes.

Treatments include:

• radiotherapy (radiation)
• chemotherapy
• targeted therapy
• immunotherapy.

Surgery is often used in the early stages of lung cancer if the tumour has not spread to other areas of the body. Chemotherapy and radiation therapy can help shrink the tumour.

Doctors from several disciplines often work together to provide treatment and care of people with lung cancer.

Supportive care is important for people with lung cancer. It aims to manage symptoms, provide pain relief, and give emotional support. It can help to increase quality of life for people with lung cancer and their families.

Stages of care

a) Early stage disease : The primary treatment for early stage lung cancer (i.e. tumour limited to the lung, with no metastatic dissemination to distant organs or lymph nodes) is surgical removal of the tumour through procedures such as lobectomy, segmentectomy, or wedge resection. Neoadjuvant therapy (chemotherapy and/or radiation therapy before surgery) can help reduce tumour size, making it more manageable for surgical removal. Adjuvant treatment (chemotherapy and/or radiation therapy) is very often recommended after surgery to reduce the risk of cancer recurrence. In cases where surgery is not feasible, radiation therapy or stereotactic body radiation therapy (SBRT) may be used as the primary treatment. Targeted therapy and immunotherapy may also be considered based on specific tumour characteristics. Individualized treatment plans should be discussed with healthcare professionals.

b) Advanced disease: The treatment for metastatic stage lung cancer, where the cancer has spread to distant organs or lymph nodes, is based on various factors, including the patient's overall health, the extent and location of metastases, histology, genetic profile, and individual preferences. The primary goal is to prolong survival, alleviate symptoms, and improve quality of life. Systemic therapies, such as chemotherapy, targeted therapy, and immunotherapy, play a crucial role in the treatment of metastatic lung cancer.

Chemotherapy is often the first-line treatment for the majority of patients around the world and involves the use of drugs that circulate throughout the body to kill cancer cells. Combination chemotherapy regimens are commonly used, and the choice of drugs depends on factors such as the histological type of the cancer and the patient's general health conditions. Targeted therapy, designed to block the signalling pathways that drive the growth of cancer cells, is an important option for patients with specific genetic mutations or biomarkers identified in their tumour. Immunotherapy, specifically immune checkpoint inhibitors, has revolutionized the treatment of metastatic lung cancer. These drugs help to stimulate the immune system to recognize and attack cancer cells. Local treatments, such as radiation therapy and surgery, may be used to manage specific metastatic sites or alleviate symptoms caused by tumour growth.

Clinical Trials

Clinical trials offer opportunities to access novel treatments or experimental therapies for patients. Participation in clinical trials helps advance medical knowledge and potentially offers new treatment options.

WHO response

WHO recognizes the significant impact of lung cancer on global health and has implemented several initiatives to address the disease comprehensively. The WHO's response focuses on tobacco control, cancer prevention, early detection, and improving access to quality treatment and care. WHO supports countries in implementing evidence-based tobacco control policies, including increasing tobacco taxes, enforcing comprehensive bans on tobacco advertising, promotion, and sponsorship, and implementing strong graphic health warnings on tobacco products.

The Organization also promotes cancer prevention strategies by advocating for healthy lifestyles, including regular physical activity, a healthy diet, and minimizing exposure to environmental risk factors. Additionally, WHO supports early detection programs and encourages countries to implement screening measures for high-risk populations to detect lung cancer at earlier stages when treatment options are more effective. Last, WHO works towards ensuring access to quality treatment and care for lung cancer patients by providing technical guidance to member states, promoting equitable access to essential cancer medicines, and fostering international collaboration to share best practices and improve cancer care outcomes.

International Agency for Research on Cancer: Lung cancer

WHO's work on tobacco cessation

WHO's work on cancer

ESMO Clinical Practice Guidelines: Lung and Chest Tumours

• Patient Care & Health Information
• Diseases & Conditions
• Lung cancer

• Bronchoscopy

In flexible bronchoscopy, a healthcare professional inserts a thin, bendable tube through the mouth or nose into the lungs. A light and a small camera on the bronchoscope allow the health professional to look inside the lungs' airways.

Lung cancer diagnosis often starts with an imaging test to look at the lungs. If you have symptoms that worry you, a healthcare professional might start with an X-ray. If you smoke or used to smoke, you might have an imaging test to look for signs of lung cancer before you develop symptoms.

Testing healthy people for lung cancer

People with an increased risk of lung cancer may consider yearly lung cancer screening using low-dose CT scans. Lung cancer screening is generally offered to people 50 and older who smoked heavily for many years. Screening also is offered to people who have quit smoking in the past 15 years.

Discuss your lung cancer risk with your healthcare professional. Together you can decide whether lung cancer screening is right for you.

Tests to diagnose lung cancer

If your healthcare professional thinks you may have lung cancer, a number of tests can be used to look for cancerous cells and to rule out other conditions.

Tests may include:

• Imaging tests. Imaging tests make pictures of the body. They can show the location and size of the lung cancer. Tests might include X-ray, MRI , CT and positron emission tomography, which also is called a PET scan.
• Sputum cytology. Sputum is the mucus that is coughed up from the lungs. If you are coughing up sputum, it can be looked at under a microscope. The sputum can sometimes show lung cancer cells.

Biopsy. A biopsy is a procedure to remove a sample of tissue for testing in a lab.

Your healthcare team can perform a lung cancer biopsy several ways. One way is bronchoscopy. During bronchoscopy, a healthcare professional passes a lighted tube with a camera down your throat into your lungs to examine the area. Special tools can be passed through the tube to collect a sample of tissue.

Mediastinoscopy also is an option. During mediastinoscopy, an incision is made at the base of your neck. Surgical tools are then inserted behind your breastbone to take tissue samples from lymph nodes.

Another option is a needle biopsy. In a needle biopsy, your healthcare professional uses X-ray or CT images to guide a needle through the skin on your chest. The needle goes into the lung tissue to collect cells that could be cancerous.

A biopsy sample also may be taken from lymph nodes or other areas where cancer has spread.

Your cancer cells will be carefully tested in a lab to find out what type of lung cancer you have. The results can help determine the likely outcome of your cancer, called the prognosis, and guide your treatment.

Tests to determine the extent of the cancer

If you're diagnosed with lung cancer, you may have other tests to see if the cancer has spread. These tests help your healthcare team find out the extent of your cancer, also called the stage. Cancer staging tests often involve imaging tests. The tests might look for signs of cancer in your lymph nodes or in other parts of your body. Your healthcare team uses the cancer staging test results to help create your treatment plan.

Imaging tests may include MRI , CT , bone scans and PET scan. Not every test is right for every person. Talk with your healthcare professional about which procedures will work for you.

The stages of lung cancer range from 1 to 4. The lowest number means that the cancer is small and only in the lung. As the cancer grows larger or spreads outside of the lungs, the numbers get higher. A stage 4 lung cancer has spread to other areas of the body.

In small cell lung cancer, the stages may be called limited or extensive. In the limited stage, the cancer affects one lung and the area around it. In the extensive stage, the cancer has spread to the other lung or to other parts of the body.

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More Information

Lung cancer care at Mayo Clinic

• Lung cancer screening
• Positron emission tomography scan
• Infographic: Lung Cancer

Treatment for lung cancer usually begins with surgery to remove the cancer. If the cancer is very large or has spread to other parts of the body, surgery may not be possible. Treatment might start with medicine and radiation instead. Your healthcare team considers many factors when creating a treatment plan. These factors may include your overall health, the type and stage of your cancer, and your preferences.

Some people with lung cancer choose not to have treatment. For instance, you may feel that the side effects of treatment will outweigh the potential benefits. When that's the case, your healthcare professional may suggest comfort care to treat only the symptoms the cancer is causing.

• Lung cancer surgery

Lung cancer surgery can involve removing a portion of the lung or the entire lung. An operation to remove the lung cancer and a small portion of healthy tissue is called a wedge resection. Removing a larger area of the lung is called segmental resection. Surgery to remove one lobe from a lung is called lobectomy. Removing an entire lung is called pneumonectomy.

During surgery, your surgeon works to remove the lung cancer and some healthy tissue around it. Procedures to remove lung cancer include:

• Wedge resection to remove a small section of lung that contains the cancer along with a margin of healthy tissue.
• Segmental resection to remove a larger portion of lung, but not an entire lobe.
• Lobectomy to remove the entire lobe of one lung.
• Pneumonectomy to remove an entire lung.

If you have surgery, your surgeon also may remove lymph nodes from your chest to test them for cancer.

Surgery may be an option if your cancer is only in the lungs. If you have a larger lung cancer, chemotherapy or radiation therapy may be used before surgery to shrink the cancer. Chemotherapy or radiation therapy also may be used after surgery if there's a risk that cancer cells were left behind or that your cancer may come back.

• Radiation therapy

Radiation therapy treats cancer with powerful energy beams. The energy can come from X-rays, protons or other sources. During radiation therapy, you lie on a table while a machine moves around you. The machine directs radiation to precise points on your body.

For lung cancer that has spread within the chest, radiation may be used before surgery or after surgery. It's often combined with chemotherapy treatments. If surgery isn't an option, combined chemotherapy and radiation therapy may be your first treatment.

For lung cancers that have spread to other areas of the body, radiation therapy may help relieve symptoms.

• Chemotherapy

Chemotherapy treats cancer with strong medicines. Many chemotherapy medicines exist. Most are given through a vein. Some come in pill form. A combination of medicines usually is given in a series of treatments over a period of weeks or months. Breaks in between are used to help you recover.

Chemotherapy is often used after surgery to kill any cancer cells that may remain. It can be used alone or combined with radiation therapy. Chemotherapy also may be used before surgery to shrink cancers and make them easier to remove.

In people with lung cancer that has spread, chemotherapy can be used to relieve pain and other symptoms.

Stereotactic body radiotherapy

Stereotactic body radiotherapy is an intense radiation treatment. This treatment aims beams of radiation from many angles at the cancer. Stereotactic body radiotherapy treatment is typically completed in one or a few treatments. Sometimes this treatment is called stereotactic radiosurgery.

Stereotactic body radiotherapy may be an option for people with small lung cancers who can't have surgery. It also may be used to treat lung cancer that spreads to other parts of the body, including the brain.

Targeted therapy

Targeted therapy for cancer is a treatment that uses medicines that attack specific chemicals in the cancer cells. By blocking these chemicals, targeted treatments can cause cancer cells to die. For lung cancer, targeted therapy may be used for people with cancer that spreads or comes back after treatment.

Some targeted therapies only work in people whose cancer cells have certain DNA changes. Your cancer cells may be tested in a lab to see if these medicines might help you.

Immunotherapy

Immunotherapy for cancer is a treatment with medicine that helps the body's immune system to kill cancer cells. The immune system fights off diseases by attacking germs and other cells that shouldn't be in the body. Cancer cells survive by hiding from the immune system. Immunotherapy helps the immune system cells find and kill the cancer cells.

For lung cancer, immunotherapy might be used after surgery to kill any cancer cells that remain. When surgery isn't an option, immunotherapy might help control the cancer.

Palliative care

Palliative care is a special type of healthcare that helps you feel better when you have a serious illness. If you have cancer, palliative care can help relieve pain and other symptoms. A healthcare team that may include doctors, nurses and other specially trained health professionals provides palliative care. The care team's goal is to improve quality of life for you and your family.

Palliative care specialists work with you, your family and your care team. They provide an extra layer of support while you have cancer treatment. You can have palliative care at the same time you're getting strong cancer treatments, such as surgery, chemotherapy or radiation therapy.

The use of palliative care with other proper treatments can help people with cancer feel better and live longer.

• Ablation therapy
• Brachytherapy
• Proton therapy
• Stop-smoking services

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Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Many people with lung cancer experience shortness of breath. Treatments such as supplemental oxygen and medicines are available to help you feel more comfortable. However, they aren't always enough.

To cope with shortness of breath, it may help to:

Try to relax

Feeling short of breath can be scary. But fear and anxiety only make it harder to breathe. When you begin to feel short of breath, choose an activity that helps you relax. Listen to music, imagine your favorite vacation spot, meditate or say a prayer.

Find a comfortable position

It may help to lean forward when you feel short of breath.

Focus on your breath

When you feel short of breath, focus your mind on your breathing. Instead of trying to fill your lungs with air, concentrate on moving the muscles that control your breathing. Try breathing through pursed lips and pacing your breaths with your activity.

Save your energy for what's important

If you're short of breath, you may become tired easily. Prioritize your tasks for the day so that you can save your energy for what needs to be done.

Tell your healthcare professional if you experience shortness of breath or if your symptoms worsen. There are many other treatments available to relieve shortness of breath.

Alternative medicine

Complementary and alternative lung cancer treatments can't cure your cancer. But complementary and alternative treatments can often be combined with your healthcare team's care to help relieve symptoms.

The American College of Chest Physicians suggests people with lung cancer may find comfort in:

Acupuncture

During an acupuncture session, a trained practitioner inserts small needles into precise points on your body. Acupuncture may relieve pain and ease cancer treatment side effects, such as nausea and vomiting.

Hypnosis is typically done by a therapist who leads you through relaxation exercises. The therapist may ask you to think pleasing and positive thoughts. Hypnosis may reduce anxiety, nausea and pain in people with cancer.

During massages, massage therapists use their hands to apply pressure to your skin and muscles. Massage can help relieve anxiety and pain in people with cancer. Some massage therapists are specially trained to work with people who have cancer.

Meditation is a time of quiet reflection in which you focus on something. It may be an idea, image or sound. Meditation may reduce stress and improve quality of life in people with cancer.

Yoga combines gentle stretching movements with deep breathing and meditation. Yoga may help people with cancer sleep better.

Coping and support

With time, you'll find what helps you cope with the uncertainty and distress of a cancer diagnosis. Until then, you may find that it helps to:

Learn enough about lung cancer to make decisions about your care

Ask your healthcare team about your cancer, including your test results, treatment options and, if you like, your prognosis. As you learn more about lung cancer, you may become more confident in making treatment decisions.

Keep friends and family close

Keeping your close relationships strong will help you deal with your lung cancer. Friends and family can provide the practical support you'll need, such as helping take care of your home if you're in the hospital. And they can serve as emotional support when you feel overwhelmed by having cancer.

Find someone to talk with

Find someone who is willing to listen to you talk about your hopes and fears. This may be a friend or family member. The concern and understanding of a counselor, medical social worker, clergy member or cancer support group also may be helpful.

Ask your healthcare team about support groups in your area. Other sources of information include the National Cancer Institute and the American Cancer Society.

Preparing for your appointment

Make an appointment with a doctor or other healthcare professional if you have any symptoms that worry you.

If your healthcare professional suspects that you have lung cancer, you'll likely be referred to a specialist. Specialists who treat lung cancer may include:

• Oncologists. Doctors who specialize in treating cancer.
• Pulmonologists. Doctors who diagnose and treat lung diseases.
• Radiation oncologists. Doctors who use radiation to treat cancer.
• Thoracic surgeons. Surgeons who operate on the lungs.
• Palliative care specialists. Doctors who treat signs and symptoms of cancer and cancer treatment.

Because appointments can be brief, it's a good idea to be prepared. Here's some information to help you get ready.

What you can do

• Be aware of any pre-appointment restrictions. At the time you make the appointment, be sure to ask if there's anything you need to do in advance, such as restrict your diet.
• Write down symptoms you're experiencing, including any that may not seem related to the reason for which you scheduled the appointment.
• Write down key personal information, including major stresses or recent life changes.
• Make a list of all medicines, vitamins or supplements you're taking and the doses. Or you may prefer to bring your medicine bottles to your appointment.
• Gather your medical records. If you've had a chest X-ray or a scan done by a different healthcare professional, try to get that file and bring it to your appointment.
• Consider taking a family member or friend along. Sometimes it can be difficult to remember all the information provided during an appointment. Someone who accompanies you may remember something that you missed or forgot.
• Write down questions to ask your healthcare team.

Questions to ask if you've been diagnosed with lung cancer

Your time with your healthcare team is limited, so preparing a list of questions can help you make the most of your time together. List your questions from most important to least important in case time runs out. For lung cancer, some basic questions to ask include:

• What type of lung cancer do I have?
• May I see the chest X-ray or CT scan that shows my cancer?
• What is causing my symptoms?
• What is the stage of my lung cancer?
• Will I need more tests?
• Should my lung cancer cells be tested for gene changes that may determine my treatment options?
• Has my cancer spread to other parts of my body?
• What are my treatment options?
• Will any of these treatment options cure my cancer?
• What are the potential side effects of each treatment?
• Is there one treatment that you think is best for me?
• Is there a benefit if I quit smoking now?
• What advice would you give a friend or family member in my situation?
• What if I don't want treatment?
• Are there ways to relieve the symptoms I'm experiencing?
• Can I enroll in a clinical trial?
• Should I see a specialist? What will that cost, and will my insurance cover it?
• Are there brochures or other material that I can take with me? What websites do you recommend?

Don't hesitate to ask other questions.

What to expect from your doctor

Be prepared to answer questions, such as:

• When did you first begin experiencing symptoms?
• Have your symptoms been ongoing or occasional?
• How severe are your symptoms?
• Do you wheeze when breathing?
• Do you have a cough that feels like you're clearing your throat?
• Have you ever been diagnosed with emphysema or chronic obstructive pulmonary disease?
• Do you take medicines for shortness of breath?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Non-small cell lung cancer. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450. Accessed Dec. 4, 2023.
• Small cell lung cancer. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462. Accessed Dec. 4, 2023.
• Niederhuber JE, et al., eds. Cancer of the lung: Non-small cell lung cancer and small cell lung cancer. In: Abeloff's Clinical Oncology. 6th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 4, 2023.
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• Lung cancer – non-small cell. Cancer.Net. https://www.cancer.net/cancer-types/lung-cancer/view-all. Accessed Dec. 4, 2023.
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• Detterbeck FC, et al. Executive Summary: Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; doi:10.1378/chest.12-2377.
• Palliative care. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1454. Accessed Dec. 4, 2023.
• Lung cancer. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/lung-cancer. Accessed Dec. 4, 2023.
• Cairns LM. Managing breathlessness in patients with lung cancer. Nursing Standard. 2012; doi:10.7748/ns2012.11.27.13.44.c9450.
• Warner KJ. Allscripts EPSi. Mayo Clinic. Jan. 13, 2020.
• Brown AY. Allscripts EPSi. Mayo Clinic. July 30, 2019.
• Searching for cancer centers. American College of Surgeons. https://www.facs.org/search/cancer-programs. Accessed Dec. 4, 2023.
• Temel JS, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. New England Journal of Medicine. 2010; doi:10.1056/NEJMoa1000678.
• Dunning J, et al. Microlobectomy: A novel form of endoscopic lobectomy. Innovations. 2017; doi:10.1097/IMI.0000000000000394.
• Leventakos K, et al. Advances in the treatment of non-small cell lung cancer: Focus on nivolumab, pembrolizumab and atezolizumab. BioDrugs. 2016; doi:10.1007/s40259-016-0187-0.
• Dong H, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine. 1999;5:1365.
• Aberle DR, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine. 2011; doi:10.1056/NEJMoa1102873.
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Stages of Non-Small Cell and Small Cell Lung Cancer

• Non-Small Cell Lung Cancer (NCSLC)
• Small Cell Lung Cancer (SCLC)
• Lung Carcinoid Tumors
• Lung Biopsy
• Lung Cancer Genomic Testing (EGFR, KRAS, ALK)
• Surgery for Lung Cancer
• Chemotherapy for Lung Cancer
• Immunotherapy for Lung Cancer
• Radiation Therapy for Lung Cancer
• Interventional Radiology for Lung Cancer
• Rehabilitation after Treatment for Lung Cancer
• Follow-Up Care & Support for Lung Cancer

Your doctor may strongly suspect you have lung cancer, or found you have it. The next step is to describe the cancer, such as the size of a tumor and if it has spread. This description is called the cancer stage. MSK’s thoracic (lung) surgeons, lung specialists, and radiologists will define your stage as quickly as possible. They will plan diagnostic procedures that will let them learn the stage of the cancer.

Staging is based on:

• The size and location of the original tumor (also called the primary tumor)
• Whether the cancer has metastasized (spread) to nearby lymph nodes
• Whether the cancer has metastasized (spread) to other organs

Staging is an important step in choosing the best treatment for you. The stage of your cancer also helps doctors predict the outcome (result) of your treatment. To do this, we may recommend you have more tests, including imaging or biopsies.  

Imaging tests to help learn the cancer stage include:

• Computed tomography (CT) scans
• Positron emission tomography (PET)/CT scans
• Magnetic resonance imaging (MRI) of the brain

Doctors use the same staging system for both non-small cell and small cell lung cancer. Small cell lung cancer usually is diagnosed at a later stage than non-small cell lung cancer. It often is diagnosed at stage 3 or 4.  

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Stages of Lung Cancer 

Stage i (1) lung cancer.

In stage 1, the tumor is only in the lung. It is bit small (4 centimeters or less). It has not spread to nearby lymph nodes or outside the chest. Most stage 1 tumors are treated with surgery.  We offer patients who cannot have surgery radiation therapy instead. Most stage 1 patients do not need chemotherapy, targeted therapy, or immunotherapy.

Stage II (2) Lung Cancer

In stage 2 lung cancer, there are larger tumors (more than 4 centimeters). Or, there are signs the cancer has spread to nearby lymph nodes, but not outside the lung.  We usually treat stage 2 lung cancer with surgery, followed by chemotherapy and targeted therapies or immune therapies. We often offer patients who cannot have surgery chemotherapy and radiation instead.

Stage III (3) Lung Cancer

In stage 3 lung cancer, there is cancer in lymph nodes of the chest further away from the lung. Or, there may be large tumors that spread to nearby lymph nodes.  Most people with stage 3 cancer have several kinds of treatment. This includes some combination of chemotherapy, surgery, radiation, targeted therapies, and immune therapies. 

Stage IV (4) Lung Cancer

In stage 4 lung cancer, there is cancer outside the chest cavity where it started.  The most common areas are the other lung, bones, brain, and the adrenal gland (a gland on top of the kidneys). Treatment depends on the tumor. It can include chemotherapy, targeted or immune therapies, or a combination.

Treatment Expertise for All Stages of Lung Cancer

MSK led the way in setting the standard of care for treating every stage of cell lung cancer. Doctors everywhere follow best practices developed at MSK. 

For example, MSK led a large research study that showed the standard treatment for stage 1 non-small cell lung cancer should be a lobectomy. In this procedure, a complete lobe of the lung is removed. There are 3 lobes in the right lung and 2 in the left. 

MSK also helped determine the best time to give chemotherapy to people who have stage 2 and 3 cancer. 

Advances made at MSK in 2021 offer new hope to people facing some of the most difficult and complex cancers. MSK researchers and doctors played a lead role in clinical trials that led to a new drug in 2021. The U.S. Food and Drug Administration (FDA) approved a drug that targets a protein, called KRAS, that fuels cancer growth. This protein may cause 1 out of 4 cases of lung cancers, but for decades it was considered “undruggable.” This treatment, called sotorasib (Lumakras™), is a new option for some people who have stage 3 or 4 non-small cell lung cancer.  

Related topics:

JEFFREY KIM, MD, HOBART LEE, MD, AND BRIAN W. HUANG, MD

Am Fam Physician. 2022;105(5):487-494

Patient information: See related handout on lung cancer , written by the authors of this article.

Published online April 1, 2022.

Author disclosure: No relevant financial relationships.

Lung cancer is the second most common cancer in men and women in the United States; however, it remains the leading cause of cancer-related death in the United States and worldwide. The most common but nonspecific symptom of lung cancer is cough. Associated symptoms, including hemoptysis or shortness of breath, or systemic symptoms, including anorexia or weight loss, greatly increase the likelihood of having lung cancer. Referral to a multidisciplinary lung cancer team, imaging, and confirmation through sputum cytology, thoracentesis, fine-needle aspiration, or mediastinoscopy are recommended. If lung cancer is confirmed, treatment options vary based on staging, histology, immunotherapy biomarker testing, and patient health status. Treatments include surgical resection, immunotherapy, chemotherapy, and/or radiotherapy. Family physicians should focus on primary prevention of lung cancer by encouraging tobacco cessation and early recognition by screening at-risk individuals and following guidelines for pulmonary nodules. As of 2021, the U.S. Preventive Services Task Force recommends annual lung cancer screening using low-dose computed tomography starting at 50 years of age in patients with a 20 pack-year history.

Lung cancer remains the leading cause of cancer-related death in the United States and worldwide; in the United States, it is the second most common cancer among men and women. 1 , 2 The majority of lung cancers are divided into two histologic types: non–small cell lung cancer (NSCLC; 84%) and small cell lung cancer (SCLC; 13%), which helps guide treatment. 3 Smoking is closely linked to 80% to 90% of lung cancer deaths, whereas radon exposure is a leading cause of nonsmoking-related lung cancer. 4 Several guidelines address the management of lung cancer, with the goal of improving patient outcomes. 5 In the United Kingdom, the National Institute for Health and Care Excellence has developed clinical pathways that were last updated in 2019, whereas in the United States, the most recent comprehensive lung cancer guideline from the American College of Chest Physicians was last updated in 2013, with more recent treatment recommendations from the National Comprehensive Cancer Network. 2 , 6 – 8

Clinical Presentation and Diagnosis

In-office evaluation.

When evaluating a patient for lung cancer, a detailed history and physical examination should be performed, including environmental and work exposures. Current smoking or history of smoking is the single most important risk factor for all types of lung cancer. 9 , 10 Concomitant chronic lung disease or exposure to radon or asbestos may increase the risk of lung cancer. 10

Patients with lung cancer typically present with symptoms, 11 the most common of which is cough. 9 , 11 Hemoptysis in combination with weight loss, loss of appetite, or shortness of breath increases the likelihood of lung cancer. 11 Table 1 provides signs and symptoms of lung cancer due to local effects, 12 and Table 2 and Table 3 show, respectively, advanced disease–displaying symptoms of distant metastases and paraneoplastic syndromes associated with lung cancer. 12

The initial evaluation for patients with a suspicion for lung cancer begins with laboratory testing, including a complete blood count, serum chemistries, calcium levels, and liver function tests, with chest radiography. 2 , 9 A normal chest radiograph alone should not be used to rule out lung cancer because just under 20% to 25% of normal chest radiographs may miss the disease. 13 , 14 Patients who have a high level of suspicion for lung cancer based on clinical assessment or initial chest radiography findings should receive computed tomography (CT) of the chest with intravenous contrast media, ideally to include the liver and adrenals. 2 , 15

PULMONARY NODULE FOLLOW-UP

Among patients presenting with incidental nodules found on radiographic imaging, follow-up for those older than 35 years is assessed based on features and risk categorization, as recommended by the Fleischner Society, updated in 2017 ( Table 4 ) . 16 , 17 New studies are emerging on the use of genomic classifiers and artificial intelligence to help facilitate clinical management of incidental nodules. 18 , 19 For patients meeting high-risk criteria and undergoing lung cancer screening, appropriate follow-up recommendations should be determined by the 2019 Lung-RADS guidelines 20 ( eTable A ) .

Diagnosis Confirmation

Patients with suspected lung cancer should be referred to a pulmonologist within a multidisciplinary thoracic oncology team to help guide workup. 6 Confirmation of the diagnosis should be made by one or more of the following methods, with further testing if suspicion is high and findings are negative: sputum cytology, thoracentesis of pleural fluid, bronchoscopy (often with endobronchial ultrasonography and/or electromagnetic navigation with or without fine-needle aspiration), or mediastinoscopy depending on local availability and expertise. 21

Staging of lung cancer follows the eighth edition of the American Joint Committee on Cancer's staging manual. 22 Staging revisions from the seventh edition were based on analysis of a database of 94,708 cases by the International Association for the Study of Lung Cancer Staging from 1999 to 2010. 23 The tumor, node, metastasis (TNM) classification describes the anatomic extent of the disease, is based on clinical and pathologic staging, and guides eventual treatment and prognosis 22 ( eTable B ) . Clinical TNM is based on history and physical examination findings, imaging, and staging procedures, and a pathologic TNM based on postsurgical histopathologic classification. The composite of these composes the TNM stage with associated prognostic stage groups I to IV 22 ( eTable C ) . TNM staging is recommended for NSCLC and SCLC for prognostic and tumor stratification purposes. 22 For NSCLC, brain imaging should be performed in stage IIA patients with consideration for stage IB patients; patients with stages III to IV disease should have magnetic resonance imaging of the brain to assess for metastases even in the absence of clinical disease. 7 , 24 Patients with any stage of SCLC should have brain imaging performed, preferably using magnetic resonance imaging. 8 In patients who may undergo curative treatment, positron emission tomography CT should be performed to assess intrathoracic lymph node involvement and guide subsequent sampling. 2 , 10

NON–SMALL CELL LUNG CANCER

The treatment of NSCLC varies based on staging, nonsquamous (usually adenocarcinoma) vs. squamous histology, and genetic and immunotherapy biomarker testing. Treatment options presented here provide an overview; however, specific regimens will vary based on the availability of treatment options and clinical experience of the multidisciplinary treatment team. Patients with advanced disease should be offered early palliative care. 7

Patients with stages I to II NSCLC are usually offered a combination of three treatments: surgery, which can include complete resection of the tumor (usually stages I and II), and mediastinal lymph node dissection or lymph node sampling; radiotherapy; and adjuvant platinum-based chemotherapy. 25 Select patients who have stage III NSCLC but do not have disease progression after chemotherapy may benefit from immunotherapy. 7 , 26 Video-assisted thoracic surgery has lower mortality and hospital length of stay compared with open thoracotomy. 27 Nonsurgical candidates can be offered radiotherapy and platinum-based chemotherapy. 28 For patients with stage IV disease, palliative care and immunotherapy with or without platinum-based chemotherapy are recommended. 7 In patients with fewer than three brain metastases, stereotactic radiotherapy or surgery with stereotactic radiotherapy is recommended. 29 With more than three brain metastases, whole brain radiation is recommended, although it may not improve neurocognitive symptoms or overall survival. 28 , 29 Radiotherapy and bisphosphonates are recommended for bone metastases to reduce pain and risk of skeletal fractures. 28 , 29

All patients who have NSCLC with nonsquamous NSCLC, mixed histology, or small-volume biopsies should be offered genetic and immunotherapy testing (e.g., broad-based, next-generation sequencing). 7 Common driver mutations, preferred treatment options, and common adverse effects are listed in eTable D . Genetic testing can predict overall prognosis and responsiveness to targeted therapies; however, U.S. Food and Drug Administration–approved therapies depend on histologic subtype, disease progression, and timing with first-line systemic chemo-therapy. 7 Standard first-line therapy for advanced NSCLC is immunotherapy with or without chemotherapy, based on PD-L1 (programmed death-ligand 1) status of expression on tumor cells. 7

PD-L1 expression (listed as a percentage between 0 and 100) of 50% or more can change the recommended immunotherapy regimen 7 , 29 , 30 ( eTable E ) .

In 2017, five-year survival for localized NSCLC was 59%, with only 5.8% for five-year survival in patients with distant metastases; however, there have been reductions in mortality since 2013 likely due to a decrease in incidence and advancements in therapies, as described previously 31 ( Table 5 22 ) .

SMALL CELL LUNG CANCER

For patients with limited-stage SCLC, the standard of care is etoposide (Etopophos) plus cisplatin chemotherapy and concurrent thoracic radiotherapy, with surgical resection offered in select patients. 8 , 32 Patients with significant comorbidities, including chronic kidney disease, may be offered an alternative carboplatin (Paraplatin)–based chemotherapy regimen with similar effectiveness. 32 For patients with extensive-stage SCLC, four to six cycles of one of several combination chemotherapy/immunotherapy regimens should be offered with maintenance immunotherapy. 8 Consolidative thoracic radiation may be considered for select patients with residual intrathoracic disease who have responded to systemic chemotherapy. 8 In patients with limited-stage SCLC, prophylactic cranial irradiation for brain metastases reduces mortality. 33 Localized palliative radiation for nonpulmonary sites, including whole brain radiotherapy for brain metastases, should be offered. 28 Patients with relapse after initial therapy have overall poor prognosis; however, several second-line systemic therapy options are available. 8 , 34 Prognosis remains poor, with only 20% to 25% five-year survival for limited-stage SCLC and less than 10% two-year survival for extensive-stage SCLC 35 ( Table 5 22 ) .

As of 2021, the U.S. Preventive Services Task Force (USPSTF) has recommended annual low-dose CT screening in adults 50 to 80 years of age who have a 20 pack-year smoking history and currently smoke or have quit smoking within the past 15 years. 36 This replaces the 2013 recommendation of annual CT screenings for patients 55 to 80 years of age with at least a 30 pack-year history. 37 The criteria for discontinuing screening are unchanged, including patients who have quit smoking for more than 15 years, have limited life expectancies (less than 10 years), or are not willing to undergo curative lung surgery. 36

The updated recommendation is based on two major randomized controlled trials, the National Lung Screening Trial and the Dutch–Belgian lung-cancer screening trial (Nederlands–Leuvens Longkanker Screenings Onderzoek). 38 , 39 Both of these trials found reductions in lung cancer mortality, with a number needed to screen to prevent one lung cancer death of 323 over 6.5 years of follow-up and 130 over 10 years of follow-up, respectively. 38 – 40 Through systematic review of these trials and modeling studies from the Cancer Intervention and Surveillance Modeling Network, the USPSTF updated its criteria for screening. 36 Earlier screening recommendations are based on studies that suggest this may help address screening disparities for certain populations, including women and Black and Hispanic people. 41 , 42 Compared with the previous USPSTF 2013 guideline, Cancer Intervention and Surveillance Modeling Network data suggest that earlier screenings would be associated with an increase in the reduction of lung cancer mortality, from a 9.8% reduction to 12.1% to 14.4%, and life-years gained, from 4,882 life-years to 6,018 to 7,596 per 100,000. 37 , 43 The American Academy of Family Physicians supports the USPSTF's grade B recommendation of lung cancer screening in adults at increased risk; however, the harms of annual CT screenings are still not well documented, and further research is needed. 44 Research gaps include evaluating potential harms associated with increased radiation exposure, identifying better technology to differentiate benign and malignant lung nodules to avoid overdiagnosis, and addressing the cost and availability of increased screening in economically disadvantaged populations. 44

Smoking Cessation and Counseling

Smoking cessation reduces morbidity and mortality in patients with lung cancer ; however, no randomized controlled trials have compared specific cessation interventions in this population. 29 , 45 Exercise training may improve exercise capacity and quality of life. 46 Nursing interventions can help patients with dyspnea, and a range of psychological interventions may improve coping skills and quality of life. 47

Although all actively smoking patients should be offered cessation support, lung cancer screening for eligible patients coupled with cessation support may be associated with higher quitting rates. 48 This combination is believed to serve as a teachable moment during a time when patients are the most receptive to quitting advice. Cessation assistance in combination with CT screening has been associated with a reduction in lung cancer–specific mortality and the potential to improve the cost-effectiveness ratio of screening. 49 , 50 Patients who quit smoking have been shown to reduce their risk of lung cancer by 39.1% after five years. 51 Patients should also be counseled that quitting smoking will reduce their risk of all second cancers by 3.5 times. 52

This article updates previous articles on this topic by Latimer and Mott 12 and Collins, et al. 53

Data Sources: A PubMed search was completed in Clinical Queries using the key terms lung cancer, diagnosis, treatment, and screening. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. The Agency for Healthcare Research and Quality Effective Healthcare Reports, the U.S. Preventive Services Task Force, the Cochrane Database of Systematic Reviews, DynaMed, Essential Evidence Plus, the National Institute for Health and Care Excellence, and the National Comprehensive Cancer Network were also searched. Search dates: April and May 2021, and January 28, 2022.

The authors thank Hamid Mirshahidi, MD, associate professor of medicine, hematology and oncology, and Laren Tan, MD, associate professor of medicine, pulmonary and critical care, Loma Linda University School of Medicine, for thoughtful advice and review of the manuscript.

Centers for Disease Control and Prevention. United States cancer statistics: data visualizations; June 2021. Accessed January 28, 2022. www.cdc.gov/cancer/dataviz

• Maconachie R, Mercer T, Navani N, et al.; Guideline Committee. Lung cancer: diagnosis and management: summary of updated NICE guidance [published correction appears in BMJ . 2019;365:I1514]. BMJ. 2019;364:l1049.

American Cancer Society. Cancer facts & figures; 2021. Accessed October 13, 2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf

Centers for Disease Control and Prevention. What are the risk factors for lung cancer? Accessed October 2021. https://www.cdc.gov/cancer/lung/basic_info/risk_factors.htm

• Wilshire CL, Rayburn JR, Chang SC, et al. Not following the rules in guideline care for lung cancer diagnosis and staging has negative impact. Ann Thorac Surg. 2020;110(5):1730-1738.
• Detterbeck FC, Lewis SZ, Diekemper R, et al. Executive summary: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):7S-37S.

National Comprehensive Cancer Network. Non-small cell lung cancer (version 04.2021). Accessed May 7, 2021. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

National Comprehensive Cancer Network. Small cell lung cancer (version 03.2021). Accessed May 5, 2021. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf

• Ost DE, Yeung S-CJ, Tanoue LT, et al. Clinical and organizational factors in the initial evaluation of patients with lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e121S-e141S.
• Alberg AJ, Brock MV, Ford JG, et al. Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e1S-e29S.
• Hamilton W, Peters TJ, Round A, et al. What are the clinical features of lung cancer before the diagnosis is made? A population based case-control study. Thorax. 2005;60(12):1059-1065.

Latimer KM, Mott TF. Lung cancer: diagnosis, treatment principles, and screening. Am Fam Physician. 2015;91(4):250-256. Accessed December 17, 2021. https://www.aafp.org/afp/2015/0215/p250.html

• Foley RW, Nassour V, Oliver HC, et al. Chest x-ray in suspected lung cancer is harmful. Eur Radiol. 2021;31(8):6269-6274.

Dwyer-Hemmings L, Fairhead C. The diagnostic performance of chest radiographs for lung malignancy in symptomatic primary-care populations: a systematic review and meta-analysis. BJR Open. 2021;3(1):20210005.

National Institute for Health and Care Excellence. Lung cancer: diagnosis and management. NICE guideline [NG122]; March 28, 2019. Accessed December 22, 2021. https://www.nice.org.uk/guidance/ng122/chapter/Recommendations

• MacMahon H, Naidich DP, Goo JM, et al. Guidelines for management of incidental pulmonary nodules detected on CT images: from the Fleischner Society 2017. Radiology. 2017;284(1):228-243.
• Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e93S-e120S.
• Lee HJ, Mazzone P, Feller-Kopman D, et al.; Percepta Registry Investigators. Impact of the Percepta genomic classifier on clinical management decisions in a multicenter prospective study. Chest. 2021;159(1):401-412.
• Massion PP, Antic S, Ather S, et al. Assessing the accuracy of a deep learning method to risk stratify indeterminate pulmonary nodules. Am J Respir Crit Care Med. 2020;202(2):241-249.

American College of Radiology. Lung-RADS version 1.1; 2019. Accessed May 18, 2021. https://www.acr.org/-/media/ACR/Files/RADS/Lung-RADS/LungRADSAssessmentCategoriesv1-1.pdf

Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e142S-e165S.

• Detterbeck FC, Boffa DJ, Kim AW, et al. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193-203.
• Goldstraw P, Chansky K, Crowley J, et al.; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(1):39-51.
• Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e211S-e250S.
• Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e278S-e313S.
• Antonia SJ, Villegas A, Daniel D, et al.; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.

Nakamura H. Systematic review of published studies on safety and efficacy of thoracoscopic and robot-assisted lobectomy for lung cancer. Ann Thorac Cardiovasc Surg. 2014;20(2):93-98.

• Tsao MN, Xu W, Wong RKS, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2018;(1):CD003869.
• Planchard D, Popat S, Kerr K, et al.; ESMO Guidelines Committee. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol . 2019; 30(5): 863–870]. Ann Oncol. 2018;29(suppl 4):iv192-iv237.
• Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al.; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.
• Howlader N, Noone AM, Krapcho M, et al. National Cancer Institute. SEER cancer statistics review (CSR), 1975–2017; April 15, 2020. Accessed January 28, 2022. https://seer.cancer.gov/csr/1975_2017
• Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30(14):1692-1698.
• Aupérin A, Arriagada R, Pignon JP, et al.; Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 1999;341(7):476-484.
• Eckardt JR, von Pawel J, Pujol J-L, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer [published correction appears in J Clin Oncol . 2007;25(22):3387]. J Clin Oncol. 2007;25(15):2086-2092.
• Jett JR, Schild SE, Kesler KA, et al. Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e400S-e419S.
• Krist AH, Davidson KW, Mangione CM, et al. Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(10):962-970.

Moyer VA. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160(5):330-338.

• Aberle DR, Adams AM, Berg CD, et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.
• de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503-513.
• Jonas DE, Reuland DS, Reddy SM, et al. Screening for lung cancer with low-dose computed tomography: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021;325(10):971-987.
• Aldrich MC, Mercaldo SF, Sandler KL, et al. Evaluation of USPSTF lung cancer screening guidelines among African American adult smokers [published correction appears in JAMA Oncol . 2019;5(9):1372]. JAMA Oncol. 2019;5(9):1318-1324.

Pinsky PF, Kramer BS. Lung cancer risk and demographic characteristics of current 20–29 pack-year smokers: implications for screening. J Natl Cancer Inst. 2015;107(11):djv226.

Meza R, Jeon J, Toumazis I, et al. Evaluation of the benefits and harms of lung cancer screening with low-dose computed tomography: a collaborative modeling study for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality; 2021. AHRQ publication 20-05266-EF-2.

American Academy of Family Physicians. Clinical preventive service recommendation. Lung cancer screening, adult. Accessed April 25, 2021. https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/lung-cancer.html

• Zeng L, Yu X, Yu T, et al. Interventions for smoking cessation in people diagnosed with lung cancer. Cochrane Database Syst Rev. 2019;(6):CD011751.
• Peddle-McIntyre CJ, Singh F, Thomas R, et al. Exercise training for advanced lung cancer. Cochrane Database Syst Rev. 2019;(2):CD012685.
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Everything You Need to Know About Lung Cancer

• Complications
• Next in Lung Cancer Guide Signs and Symptoms of Lung Cancer

Lung cancer is cancer that starts in your lungs. It is the leading cause of cancer death among men and women.

Finding lung cancer early before it spreads improves your chances of beating the disease. Certain groups are advised to have routine lung cancer screenings to improve their chances of finding the problem early.

This article describes lung cancer types, symptoms, causes, diagnosis, stages, and treatments.

South_agency / Getty Images

Types of Lung Cancer

There are several types of lung cancer. The main types of lung cancer look, grow, and spread differently. Lung cancers are classified by the type of cell in which the cancer began.

Small Cell Lung Cancer

Small cell lung cancer accounts for up to 15% of all lung cancers. It comprises smaller-sized cells that grow and spread quickly. This type of lung cancer often originates in the bronchi near the center of your chest.

The two types of small cell lung cancer are:

• Small cell carcinoma: Small cell carcinoma is the most common type of small cell lung cancer. Its tumor cells look flat under a microscope.
• Combined small cell carcinoma: Combined small cell carcinoma involves tumors comprised of small cell carcinoma cells and non-small cell lung cancer cells.

Non-Small Cell Lung Cancer

Up to 85% of lung cancers are non-small cell lung cancers. It is the most common type of lung cancer. Non-small cell lung cancer usually grows and spreads slower than small cell lung cancer.

There are several types of non-small lung cancer that originate from different types of lung cells. They include the following:

• Adenocarcinoma : Adenocarcinomas start in the cells that normally secrete substances like mucus and help us breathe. They are often found in the outer region of your lungs.
• Squamous cell carcinoma : Squamous cell carcinomas are usually found in cells in the tissues in the center of your lung next to a bronchus, one of the air tubes that lead from the trachea (windpipe) to the lungs.
• Large cell carcinoma : Large cell carcinomas originate in the cells that comprise the outer lining of your lungs. It is the most likely subtype of non-small cell lung cancer to spread.

Other Types of Cancer in the Lungs

In addition to the main types of lung cancer, the following tumors can occur in your lungs:

Lung carcinoid tumors : Lung carcinoid tumors originate in neuroendocrine cells , a special type of lung cell. Most of these rare tumors grow slowly.

Other lung tumors: The following types of lung cancers are treated differently from other, more common lung cancers:

• Adenoid cystic carcinomas
• Benign lung tumors

Cancers that spread to the lungs: Cancers that originate in other organs like the kidney , breast, pancreas, or skin, can metastasize to the lungs but they are not lung cancers. Treatment for these cancers is based on the primary site where cancer started.

Lung Cancer Symptoms

Lung cancer symptoms often go undetected in the early stages of the disease. Symptoms usually don't occur until the disease spreads.

When they appear, lung cancer symptoms are often ignored or attributed to another condition because they are not unique to lung cancer. As a result, it is common for people to wait to consult a healthcare provider until symptoms worsen and the disease spreads.

Early Signs of Lung Cancer

Early signs of lung cancer can often appear to be other conditions. However, waiting to get a diagnosis could jeopardize your treatment options. The American Cancer Society advises that you consult your healthcare provider if you experience any of the following early signs of lung cancer:

• A cough that persists or worsens
• Blood or rust-colored mucus/phlegm in your cough
• Chest pain that worsens with coughing, deep breathing, or laughing
• Shoulder pain
• Loss of appetite
• Unexplained weight loss
• Shortness of breath
• Hoarseness or changes in voice
• Feeling tired or weak
• Persistent lung infections like bronchitis (inflammation of the bronchi walls) and pneumonia that don't improve or keep occurring

Late Symptoms

As cancer spreads, it can affect other parts of your body and can cause any of the following symptoms:

• Bone pain , especially in the hips or back
• Headaches or seizures
• Weakness , numbness , or swelling of an arm or leg
• Dizziness /balance problem
• Jaundice (yellowing of the eyes and skin)
• Swelling of lymph nodes in the neck or above the collarbone
• Eyelid drooping or weakness
• Difficulty swallowing
• Facial paralysis (not being able to move the muscles of the face) or swelling

How Long Can You Have Lung Cancer Without Knowing?

Most people with lung cancer can live with the disease for months or years before they realize that they are ill. Obvious physical changes usually don't occur until the disease progresses.

What Causes Lung Cancer?

There are several potential causes of lung cancer. It can also occur without a clear understanding of its cause.

Cigarette smoking ranks as the leading cause of lung cancer. It accounts for up to 90% of lung cancer cases. Smoking cigarettes makes you 15 to 30 times more likely to develop lung cancer than someone who doesn't smoke.

The following characteristics can also increase your risk for lung cancer:

• Smoking other types of tobacco like pipes or cigars
• Breathing secondhand smoke from cigarettes, pipes, or cigars
• Personal or family history of lung cancer
• Exposure to the following substances at home or work:
• Diesel exhaust
• Radiation therapy to the chest

While smoking is a known cause of lung cancer, there is no clear evidence that some other practices, like electronic cigarettes (e-cigarettes) or marijuana, cause lung cancer. However, both vaping and smoking can cause damage to your lungs and may increase your risk of lung damage and other diseases, potentially increasing your risk of lung cancer.

How Smoking Causes Lung Cancer

Smoking ranks as the leading cause of lung cancer, causing 85% of lung cancer cases. Research indicates that smoking causes lung cancer by creating cell mutations from the carcinogens contained in cigarette smoke. When cells develop cancerous mutations, they continue to divide and grow abnormally.

How Is Lung Cancer Diagnosed?

Getting an accurate lung cancer diagnosis is key to getting the right lung cancer treatment as early as possible. Your healthcare uses the following tests to make a diagnosis:

Physical Examination:

A physical examination includes taking a thorough medical history and family history. Your healthcare provider determines your risk of lung cancer and investigates your symptoms.

Imaging tests use X-rays, sound waves, magnetic fields, or radioactive substances to allow your healthcare provider to see the inside of your body. The following types of imaging tests are used:

• Chest X-ray ; A chest X-ray is the first test performed when lung cancer is suspected. It can show a lung mass of abnormal lung cells or a smaller spot called a lung nodule , though it can't determine whether the mass is benign or malignant.
• Computed tomography (CT) scan : A CT scan uses a series of X-rays to create a three-dimensional view of your lungs so your healthcare provider can look at the lungs from more than one angle.
• Magnetic resonance imaging (MRI) : An MRI uses radio waves and strong magnets instead of X-rays to look for the spread of lung cancer.
• Positron-emission tomography (PET) scan : A PET scan uses the injection of a short-acting radioactive substance, called a radiotracer, which collects in cancer cells. A tunnel-like device is used to detect the emitted radiation and form pictures.

Lung Biopsy

When imaging tests indicate the presence of lung cancer, a lung biopsy is the next step in getting a diagnosis. This involves removing a tissue sample from the area where lung cancer is suspected. The following types of lung biopsy are used:

• Fine needle aspiration biopsy (uses a thin needle to extract lung tissue)
• Endoscopic ultrasound (uses a camera and sound waves to produce live images of your lungs and lymph nodes)

Bronchoscopy

A bronchoscopy uses a bronchoscope, a narrow tube with a light and camera on one end, to get an internal view of your respiratory system. It is inserted through the nose or mouth and guided down the windpipe.

Endobronchial Ultrasound

An endobronchial ultrasound combines bronchoscopy with an ultrasound probe to examine the mediastinum.

Thoracentesis

Thoracentesis involves using a large needle to remove a small amount of fluid from the pleural cavity , the space between your lungs.

Mediastinoscopy

A mediastinoscopy is a surgical procedure that uses a narrow scope, called a mediastinoscope, inserted through your chest wall to examine the mediastinum , the area between your lungs.

Labs and Tests

The following labs and tests are used to diagnose lung cancer:

• Complete blood count (CBC) , which can determine changes in your blood caused by lung cancer
• Pulmonary function test , which determines lung capacity
• Sputum cytology , which involves using a microscope to examine a sample of sputum

Lung Cancer Screening

Lung cancer screening involves testing for a disease when thee aren't symptoms or history. The only recommended screening test for lung cancer is a low-dose computed tomography (CT) scan. The scan is noninvasive, painless, and highly accurate.

Recommendations for Lung Cancer Screenings

The American Lung Association advises screening for lung cancer based on recommendations from the U.S. Preventive Services Task Force (USPSTF), a volunteer, independent panel of experts in evidence-based medicine and disease prevention.

Lung cancer screening with low-dose CT annually is advised for adults with all of the following characteristics:

• Between the ages of 50 and 80 years
• A 20 pack-year smoking history (pack-years are calculated by multiplying the number of packs smoked per day times the number of years smoked)
• Currently smoke or have quit within the past 15 years

If you are included in this group, screening can cease if you have not smoked for 15 years or have a health problem that limits your life expectancy or your eligibility for lung surgery.

Lung Cancer Stages

Lung cancer staging defines if and how much your lung cancer has spread. It helps your healthcare providers determine your treatment plan. It is easier to treat lung cancer at an early stage than when the disease is in advanced stages.

Lung cancer staging is based on the following factors:

• The location of your lung cancer
• The size and extent of your lung cancer tumors
• If and where the lung cancer spread
• Lymph node involvement

In the United States, lung cancer is staged using the American Joint Committee on Cancer’s TNM system which involves the following areas:

• Size and tumor number (T)
• Lymph node involvement (N)
• If and to what extent the liver cancer has metastasized (M)

The two main types of lung cancer, non-small cell lung cancer and small lung cell cancer, are staged differently according to the following criteria:

Non-Small Cell Lung Cancer Stages:

Stage 0 (carcinoma/tumor in-situ)

• Only present in the top lining of your lung
• No spread to other parts of your body
• Divided into substages 1A and 1B, based on tumor size
• No spread to the lymph nodes or other parts of your body
• Divided into substages 2A and 2B, based on tumor size, location, and lymph node involvement
• No spread to other parts of the body
• Divided into substages 3A, 3B, and 3C, based on tumor size, location, and how far it has spread
• Spread of cancer to the lymph nodes in the mediastinum
• The most advanced form of lung cancer
• Cancer has spread to the lining of your lung or other areas of your body

Small Cell Lung Cancer Stages

Limited stage:

• Lung cancer in only one lung
• With or without the spread to the lymph nodes in your mediastinum

Extensive stage:

• Lung cancer spread from the affected lung to the opposite lung or distant organs

The formal stage of your lung cancer doesn't change over time, even if your cancer improves or progresses. Rarely, cancer might be restaged after a period of remission.

Lung Cancer Treatment

Your options for lung cancer treatment are determined by your lung cancer stage, lung cancer type, and treatment goals. Depending on your circumstances, you may need more than one type of treatment.

Lung cancer surgery involves removing portions of your lung. This procedure is regarded as the best option when lung cancer is limited to one area and hasn't spread. One of the following techniques is used:

• Pneumonectomy : Removal of the entire affected lung
• Lobectomy : Removal of one of the sections, or lobes) of an affected lung
• Wedge resection : Removal of the tumor and a wedge-shaped area of the lung tissue surrounding the tumor
• Sleeve resection : Removal of a lobe and part of the bronchus
• Segmentectomy : Removal of a segment of a lobe that takes less tissue than a lobectomy but more tissue than a wedge resection

Radiation therapy for lung cancer uses powerful, high-energy X-rays to stop the growth or kill cancer cells from outside your body to kill cancer cells.

Chemotherapy

Chemotherapy for lung cancer involves the intravenous administration of drugs to kill or stop the growth of cancer cells,

Immunotherapy

Immunotherapy uses the abilities of your body's immune system, which protects you from foreign agents, to help it recognize cancer cells and kill them.

Targeted Drug Therapy

Targeted drug therapy uses treatments that interrupt the growth and normal function of cancer cells while reducing damage to healthy cells.

Radiofrequency Ablation

Radiofrequency ablation is an image-guided technique that uses high-energy radio waves to heat a tumor and destroy cancer cells.

Complications of Lung Cancer

There are many potential complications of lung cancer. These problems can occur as a result of disease progression or the therapies used to treat the disease.

Common complications of lung cancer include the following:

• Chemotherapy -induced infection : Chemotherapy reduces the number of white blood cells that fight infection, making your body susceptible to neutropenia , a condition that increases your risk of infections like pneumonia and sepsis.
• Malignant pleural effusion : A malignant pleural effusion occurs when there is a buildup of fluid that contains cancer cells in the pleural cavity , the area between the membranes that line your lungs.
• Hypercalcemia: Hypercalcemia, abnormally high calcium levels in your blood, occurs when cancer spreads to your bones.
• Depression : While depression is common in many types of cancer, people with lung cancer may have a higher risk of depression because of the disease's stigma or a likelihood of a poor prognosis.
• Malignant pericardial effusion : Malignant pericardial effusion occurs when the pericardium, the sac surrounding the heart, becomes filled with extra fluid.
• Blood clots : Blood clots in the pelvis or legs can develop in the deep veins of your arms or legs and cause severe swelling and pain.
• Pulmonary hemorrhage : A pulmonary hemorrhage is a sudden bursting of a major blood vessel in your lungs. It occurs when a tumor infiltrates a blood vessel and weakens it.
• Spinal cord compression : Spinal cord compression can develop when lung cancer spreads to the bones of your spine, making them weaken and at risk of collapsing.
• Superior vena cava syndrome: Superior vena cava syndrome is a group of problems that occur when tumors in the upper portion of your lungs press directly on the superior vena cava, the large vein that returns blood away from your upper body to your heart.

Can You Prevent Lung Cancer?

Lung cancer can't always be prevented. Some cases of lung cancer occur in people who don't smoke or have any risk factors. However, taking the following steps can help lower your risk of lung cancer:

• If you smoke, quit. If you don't smoke, don't start.
• Avoid exposure to secondhand smoke.
• Avoid exposure to radon by checking your home.
• Avoid or limit exposure to cancer-causing substances at home and at work.
• Eat a healthy diet that includes plenty of fruits and vegetables.
• Exercise regularly.
• Get screened for lung cancer as advised.

Outlook for Lung Cancer

Your lung cancer prognosis is a forecast or prediction of the way your healthcare provider expects your lung cancer and treatment to evolve. While the outlook for your lung cancer is based on the details of your condition, it is calculated on the experiences of large groups of people over many years, not individual cases. Your experience with lung cancer can differ from the prognosis you receive.

Your prognosis depends on the following factors:

• Stage of lung cancer
• The type of cancer and where it is in your body
• Weight loss
• Performance status, how well you can do your daily activities
• Overall health
• Genetic changes to your cancer cells

The five-year survival rate for lung cancer is 56% for cases diagnosed when the cancer is limited to your lungs. However, because lung cancer often begins without symptoms, only 16% of lung cancer cases are identified in the early stage of the disease.

Living With Lung Cancer: Support and Resources

Dealing with a lung cancer diagnosis requires more than medical care. Research indicates that people with lung cancer experience poor quality of life and an increased rate of psychological distress.

Having a strong support system can make a difference in your physical and mental health. Accept the help of family and friends who are willing to handle everything from meal preparation to driving you to and from appointments. Trying to do everything on your own can leave you feeling overwhelmed and exhausted.

If you're feeling overwhelmed, ask for a palliative care support visit. This involves meeting with a team of specialists, including a social worker, a nurse, and a healthcare provider, who can address the full range of concerns involved in your cancer treatment.

Some of the most valuable resources are those that involve others who understand what you are experiencing. Check out lung cancer social media blogs by people who are sharing their cancer journeys.

You can include an online or local cancer support group. You may benefit most from being with people who understand what you are experiencing. Some options for support groups include the following organizations:

• LUNGevity Support Community
• Inspire: Lung Cancer Survivors Community
• The Cancer Survivors Network

Lung cancer can be a severe and deadly type of cancer. It ranks as the leading cause of cancer-related deaths.

Lung cancer most often affects people with a history of smoking. However, you can get this disease even if you don't smoke or have other known risk factors.

Since many people don't have symptoms until their lung cancer spreads to other parts of their body, lung cancer is often deadly and hard to treat. However, getting an early diagnosis can improve your chances of having the best outcomes.

While there are several treatment options, they are not always effective in killing this fast-moving disease. Lung cancer clinical trials may provide more options if current treatments are not helpful.

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By Anna Giorgi Giorgi is a freelance writer with more than 25 years of experience writing health and wellness-related content.

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• Published: 22 May 2019

Presentation of lung cancer in primary care

• D. P. Weller 1 ,
• M. D. Peake 2 &
• J. K. Field 3  

npj Primary Care Respiratory Medicine volume  29 , Article number:  21 ( 2019 ) Cite this article

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• Respiratory signs and symptoms
• Signs and symptoms

Survival from lung cancer has seen only modest improvements in recent decades. Poor outcomes are linked to late presentation, yet early diagnosis can be challenging as lung cancer symptoms are common and non-specific. In this paper, we examine how lung cancer presents in primary care and review roles for primary care in reducing the burden from this disease. Reducing rates of smoking remains, by far, the key strategy, but primary care practitioners (PCPs) should also be pro-active in raising awareness of symptoms, ensuring lung cancer risk data are collected accurately and encouraging reluctant patients to present. PCPs should engage in service re-design and identify more streamlined diagnostic pathways—and more readily incorporate decision support into their consulting, based on validated lung cancer risk models. Finally, PCPs should ensure they are central to recruitment in future lung cancer screening programmes—they are uniquely placed to ensure the right people are targeted for risk-based screening programmes. We are now in an era where treatments can make a real difference in early-stage lung tumours, and genuine progress is being made in this devastating illness—full engagement of primary care is vital in effecting these improvements in outcomes.

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Introduction.

Lung cancer poses a significant public health burden around the world; it is the most common cause of cancer mortality in the UK and it accounts for >20% of cancer deaths. 1 There is significant variation in survival rates around the world and this has been largely attributed to the stage at which the cancer is diagnosed. 2 The International Cancer Benchmarking Partnership has demonstrated that survival rates in the UK lag behind those of other countries, and late diagnosis is thought to be a major underlying factor. 3 , 4 Importantly, patients with early-stage disease have a much better prognosis; stage 1 non-small-cell lung cancer can have a 5-year survival rate as high as 75%. 5 Even within the UK, however, there is wide variation in lung cancer survival rates and in the proportion of patients diagnosed with early-stage disease. 6

In the UK, most cancers present symptomatically in primary care (most commonly to a general practitioner, or ‘GP’, the medical lead of a primary care team), and the diagnosis is made after a referral for either investigations or directly to secondary care. 7 Many of the symptoms of lung cancer are very common but non-specific in primary care practice: these include chest pain, cough and breathlessness; 8 hence, lung cancer poses a very significant diagnostic challenge—a primary care practitioner (PCP) working full time is likely to only diagnose 1 or 2 cases per year. Further, lung cancer often emerges on a background of chronic respiratory disease and symptoms of chronic cough—typically in patients who smoke. It can be very difficult to identify changes in these chronic symptoms that might indicate the development of a lung tumour.

Smoking remains the principal aetiological factor and smoking cessation is the key public health initiative to reduce mortality from this disease; 9 indeed, at almost any age smoking cessation can produce health benefits. Hence, public health campaigns to promote smoking cessation, supplemented by strategies in primary care based on nicotine replacement therapies should be encouraged. 10 The role of e-cigarettes is not yet fully understood, 11 although any strategy that reduces exposure to tobacco smoke has a potential for producing significant benefits.

How do patients respond to lung cancer symptoms?

There is a significant body of research around patient response to symptoms that might potentially indicate lung cancer. Because symptoms often present within the context of chronic respiratory symptomatology, changes associated with the development of a tumour may go un-noticed or be dismissed. 8 It is known that patients often delay their help seeking through a range of psychological mechanisms including denial and nihilism—hence, there can often be significant delays before patients present to primary care. 12 , 13

There is evidence for variation in the timeliness of presentation of lung cancer in between countries; people with lung cancer often have symptoms for a considerable period of time before they present to primary care and this is a major source of delay in the diagnostic process with potential adverse impact on survival; 14 , 15 this patient interval does, however, vary between studies. It is important that PCPs understand some of the psychological mechanisms that either promote or inhibit early presentation among their patients.

Public awareness of lung cancer

Over the past few years, there have been campaigns run throughout the UK designed to make the public more aware of symptoms associated with lung cancer—for example the ‘Be clear on Cancer’ campaign run by Public Health England and ‘Diagnose Cancer Early’ in Scotland 16 , 17 (see Fig. 1 ). These campaigns have demonstrated an ability to diagnose additional cancers and effect modest increases in the proportion of patients having tumours diagnosed at stages where they are amenable to resection. 18 , 19

Posters used in the ‘Be Clear on Cancer’ campaign

Of course, lung cancer early detection programmes need to be focussed on the hard-to-reach population and those who will benefit most from involvement; there are often concerns expressed over burdening services with patients with insignificant symptoms 18 and an emerging consensus that all stakeholders should be closely engaged in the campaigns. Nevertheless, available evidence suggests that lung cancer could be diagnosed earlier through these public awareness campaigns, 19 particularly when associated with systems to help primary care physicians risk stratify their patients for lung cancer more effectively—indeed, further work to identify patients who might benefit from targeted interventions should be a priority.

Community-based social marketing interventions have a potential key role; 20 they can increase the likelihood of patients attending PCPs and increase primary care diagnostic activity (such as chest X-ray referrals)—as well as increases in lung cancer diagnostic rates. The level of suspicion at which PCPs consider a referral is a key factor in response to these campaigns—and there are concerns over ‘system overload’ through encouragement to present with symptoms. 13 Ideally, campaigns might preferentially target those at greater risk of lung cancer, such as people with significant smoking histories or occupational exposure.

Primary care response to lung cancer symptoms

In the UK, GPs will on average only diagnose one or two cases of lung cancer per year (if they are in full-time practice). 21 However, during that year, GPs will see hundreds of patients with common symptoms, such as cough, breathlessness and chest pain—hence, there are significant difficulties in identifying, diagnosing and referring these patients in a timely manner.

The 2015 NICE lung cancer guidelines on recognition and referral 22 have underpinned some important strategies to enhance timely lung cancer diagnosis; in many regions of the UK, there are now accelerated diagnostic pathways that assist GPs in identifying and referring patients appropriately. 23 Audit data demonstrate that there are typically several consultations prior to a diagnosis of lung cancer being made. 24 Evidence from significant event analysis in the UK has suggested that there is timely recognition and referral of symptoms in primary care; 25 longer intervals are typically attributed to factors such as X-rays being reported as normal, patient-mediated factors and presentations complicated by co-morbidity. The importance of safety netting has also been emphasised in presentations where a diagnosis of lung cancer is possible. 26

There needs to be continued work to counteract the ‘nihilism’ associated with lung cancer; PCPs are very well aware of patients who may suspect they have lung cancer but fail to present either because they blame themselves (through a history of smoking) or because they believe that if a cancer is diagnosed there is little that can be done about it. 27 This, coupled with the tendency for patients in the UK to be concerned about ‘bothering the doctor’, 28 can have detrimental effects on early diagnosis.

While public campaigns can do much to overcome barriers to presentation, it is vital that PCPs become more pro-active in achieving more timely diagnosis in their practice populations. It is been recommended that they should recognise the psychological mechanisms that might underlie patient delay and tackle nihilistic attitudes through educational and motivational strategies. 29 Indeed, there is cause for cautious optimism with new treatments, and this should be conveyed to patients; for example, the use of stereotactic radiotherapy and volume-sparing surgery means that patients who previously could not be offered curative treatment due to co-morbidities are often now eligible. 30

Audits that systematically identify at-risk patients who may be failing to present are a potential way forward; interventions which identify and target high-risk patients appear feasible in primary care. 31 Crucially, patients should be reassured that PCPs are always happy to see them if they are worried about potential cancer symptoms.

Risk assessment and lung cancer

It is vital in assessing lung cancer risk to look carefully at lifestyle factors and past medical history; only one in seven cases of lung cancer occur in people who have never smoked, and the presence of chronic obstructive pulmonary disease doubles the risk independent of smoking history. 32 A previous history of head and neck, bladder and renal cancers and other factors such as exposure to asbestos or living in high radon exposure areas are all important in lung cancer risk assessment. Family history produces an excess of risk and should be included in risk assessment—as should the symptom of fatigue, a common feature of lung cancer. Cancer decision support tools such as the ‘Caper’ instrument or ‘Q cancer’ have emerged in recent years in the UK, enabling GPs to make assessments of cancer risk based on presenting symptoms; 33 , 34 they have been incorporated into clinical systems in primary care with mixed results.

Beyond these symptom-based models, a number of lung cancer risk models have been developed based on validated epidemiological criteria—for example, the Liverpool Lung Project (LLP) risk model 35 ( www.MyLungRisk.org ), which was subsequently used in the UK Lung Cancer Screening Trial. 36 The LLP v2 risk model has also been used in the Liverpool Healthy Lung project, 37 which has accommodated the risk model within primary care practice and produced risk assessments that are useful in clinical decision making is now running into its third year. The Manchester lung cancer pilot study 38 has used the PLCO 2012 risk prediction model 39 and the recent Yorkshire Lung cancer screening trial 40 is using both the LLP v2 and the PLCO 2012 risk models. Models such as these provide a systematic way of assessing lung cancer risk, taking into account a range of factors, including smoking duration, previous respiratory disease, family history of lung cancer, age, previous history of malignancy and asbestos exposure.

Risk stratification in primary care is clearly a key priority. We need to look at instruments such as the LLP model and identify ways that lung cancer risk stratification can be made easy and convenient in primary care. At present, it is not possible to recommend a specific risk assessment tool for use in primary care; current ongoing research in primary care is externally validating existing tools and will compare their efficacy. 41 Acceptability and feasibility also need to be examined; complex algorithms that place extra burden on practitioners are unlikely to succeed. However, we do need to ensure that the basic risk prediction parameters are correctly documented in primary care, so they can be utilised in any future national lung cancer screening programme approved by the UKNSC. We also need a better understanding of ways to maximise benefits of these models—while minimising potential harms such as over-medicalisation, anxiety and false reassurance. 42 Machine learning or neuro-linguistic programming, whereby data from multiple practice-based and external sources might be examined to develop risk estimates, are also likely to play a significant role in the future. 43

Diagnostic pathways

Early diagnosis lung cancer clinics based on multi-disciplinary teams (MDTs) are an ideal option for expediting diagnosis—ideally with an urgent (2-week wait) referral; 44 there is good evidence that these specialist MDT clinics are associated with improved outcomes. Another important consideration is involving the whole primary care team and including other practitioners such as pharmacists who see a lot of patients with, for example, repeat purchases of cough medicine. There has been a push to change referral practices in some parts of the UK—for example, to lower the threshold that PCPs refer for chest X-ray 45 and to encourage practitioners to repeat the investigation after a few months if symptoms persist; critically a normal chest X-ray does not exclude diagnosis of lung cancer. One highly successful programme in Leeds included the option for people to self-refer for chest X-rays in walk-in clinics 19 —a crucial element was the engagement of primary care in the design and implementation of the programme.

Diagnostic pathways have been closely examined and tested over recent years, an example being CRUK’s ACE programme (accelerate, coordinate and evaluate) initiated in June 2014 in England and Wales. 23 Patients often have complex pathways that can lead to delays; important initiatives in the ACE programme and elsewhere include risk-stratified computed tomographic (CT) screening criteria for ‘straight to CT’ referrals following normal chest X-rays and a focus on diagnostic paths for patients with vague symptoms.

Work needs to continue on diagnostic pathways that might expedite lung cancer diagnosis. It is important, for example, that we get more evidence on the impact or potential impact of direct access to investigations such as spiral CT from primary care—at present, there is not sufficient evidence or resource to universally implement this strategy, and there is evidence that delays can occur in primary care (for example, through ordering too many chest X-rays. 46 Nevertheless, GPs in the UK often indicate that direct access to investigations would help streamline diagnosis. 7

Lung cancer screening

A major challenge for primary care is the lack of symptoms in very early stage lung cancer, highlighting the importance of examining the potential of screening. The US National Lung Cancer Screening Trial, which used low-dose CT scanning in high-risk patients, showed a 20% reduction in lung cancer-specific mortality and almost a 7% reduction in all-cause mortality—and the US Preventive Task Force on Lung cancer Screening recommended that lung cancer screening should be implemented in high-risk populations. 47 , 48 Accordingly, Medicare agreed to pay for lung cancer screening within certain criteria—however, the current uptake in the US is only ~2% of high-risk individuals.

The recent report on the NELSON trial at the World Lung Cancer Conference, Toronto 49 has demonstrated an encouragingly low rate of false positives and a mortality benefit of 26% in men and between 39% and 61% in women—depending on the number of years of follow-up (i.e. 8–10 years). These results provide further impetus for the introduction of spiral CT scanning for individuals at high risk of cancer in the UK. Figure 2 illustrates the process for identifying an appropriate screening population, recruiting them and implementing screening—in many ways more complex than existing cancer screening programmes where recruitment is based principally on age and gender.

Levels of evidence for the implementation of lung cancer screening in Europe. The colour codes refer to the current status March 2019; traffic lights: green—ready, amber—borderline evidence. Underlined text indicates particular relevance for primary care 53

If we are, indeed, on the cusp of a new screening programme, there are important implications for primary care; the key issue in lung cancer screening is identifying the right patients to invite. This is a task that would involve primary care which currently lacks the systems and the processes to undertake the kind of population- based lung cancer risk assessment required. It is important, therefore, that we plan for an era where high-risk patients are screened for lung cancer (implemented, ideally, in tandem with smoking cessation programmes). We should be refining current strategies to risk stratify patients in primary care in preparation for this new era. 50 , 51 Screening alone, however, is not the total answer and a high level of awareness in both the public and the primary care community will remain vital elements in what needs to be a multi-pronged approach. 52

Conclusions and recommendations

Mortality rates for lung cancer remain stubbornly high; if we are to improve lung cancer outcomes, it is important that early diagnosis and screening efforts achieve their maximum potential. We need to:

identify ways of raising awareness of symptoms potentially associated with lung cancer in ways that encourage people at higher risk to come forward—this will require refinement of the messages delivered in awareness-raising strategies

counter the nihilistic beliefs often associated with lung cancer—early diagnosis CAN lead to improved outcomes

continually strive to improve the primary care response to patients with symptoms of lung cancer, supported by better diagnostic pathways and risk-based decision support

identify ‘fail-safe’ mechanisms by which patients advised to ‘watch and wait’ are not lost to follow-up; it is vital that patients understand these safety netting and follow-up advice

ensure that the basic risk prediction parameters are correctly documented in primary care, so they can be utilised in any future national lung cancer screening programme approved by the UKNSC

refine methods to implement lung cancer risk assessment model approaches; this is key to improving diagnosis of early lung cancer—and we should aim for risk estimates that can be readily incorporated into the various kinds of practice software used in primary care practices

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Weller, D.P., Peake, M.D. & Field, J.K. Presentation of lung cancer in primary care. npj Prim. Care Respir. Med. 29 , 21 (2019). https://doi.org/10.1038/s41533-019-0133-y

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Lung Cancer: Clinical Presentation and Diagnosis

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• PMID: 29313654

In the absence of screening, most patients with lung cancer are not diagnosed until later stages, when the prognosis is poor. The most common symptoms are cough and dyspnea, but the most specific symptom is hemoptysis. Digital clubbing, though rare, is highly predictive of lung cancer. Symptoms can be caused by the local tumor, intrathoracic spread, distant metastases, or paraneoplastic syndromes. Clinicians should suspect lung cancer in symptomatic patients with risk factors. The initial study should be chest x-ray, but if results are negative and suspicion remains, the clinician should obtain a computed tomography scan with contrast. The diagnostic evaluation for suspected lung cancer includes tissue diagnosis, staging, and determination of functional capacity, which are completed simultaneously. Tissue samples should be obtained using the least invasive method possible. Management is based on the individual tumor histology, molecular testing results, staging, and performance status. The management plan is determined by a multidisciplinary team consisting of a pulmonology subspecialist, medical oncology subspecialist, radiation oncology subspecialist, and thoracic surgeon. The family physician should remain involved with the patient to ensure that patient priorities are supported and, if necessary, to arrange for end-of-life care.

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Presentation of lung cancer in primary care

D. p. weller.

1 Usher Institute, University of Edinburgh, Edinburgh, UK

M. D. Peake

2 Centre for Cancer Outcomes, University College London Hospitals Cancer Collaborative, University of Leicester, NCRAS/PHE, London, UK

J. K. Field

3 Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, The University of Liverpool, Liverpool, UK

Survival from lung cancer has seen only modest improvements in recent decades. Poor outcomes are linked to late presentation, yet early diagnosis can be challenging as lung cancer symptoms are common and non-specific. In this paper, we examine how lung cancer presents in primary care and review roles for primary care in reducing the burden from this disease. Reducing rates of smoking remains, by far, the key strategy, but primary care practitioners (PCPs) should also be pro-active in raising awareness of symptoms, ensuring lung cancer risk data are collected accurately and encouraging reluctant patients to present. PCPs should engage in service re-design and identify more streamlined diagnostic pathways—and more readily incorporate decision support into their consulting, based on validated lung cancer risk models. Finally, PCPs should ensure they are central to recruitment in future lung cancer screening programmes—they are uniquely placed to ensure the right people are targeted for risk-based screening programmes. We are now in an era where treatments can make a real difference in early-stage lung tumours, and genuine progress is being made in this devastating illness—full engagement of primary care is vital in effecting these improvements in outcomes.

Introduction

Lung cancer poses a significant public health burden around the world; it is the most common cause of cancer mortality in the UK and it accounts for >20% of cancer deaths. 1 There is significant variation in survival rates around the world and this has been largely attributed to the stage at which the cancer is diagnosed. 2 The International Cancer Benchmarking Partnership has demonstrated that survival rates in the UK lag behind those of other countries, and late diagnosis is thought to be a major underlying factor. 3 , 4 Importantly, patients with early-stage disease have a much better prognosis; stage 1 non-small-cell lung cancer can have a 5-year survival rate as high as 75%. 5 Even within the UK, however, there is wide variation in lung cancer survival rates and in the proportion of patients diagnosed with early-stage disease. 6

In the UK, most cancers present symptomatically in primary care (most commonly to a general practitioner, or ‘GP’, the medical lead of a primary care team), and the diagnosis is made after a referral for either investigations or directly to secondary care. 7 Many of the symptoms of lung cancer are very common but non-specific in primary care practice: these include chest pain, cough and breathlessness; 8 hence, lung cancer poses a very significant diagnostic challenge—a primary care practitioner (PCP) working full time is likely to only diagnose 1 or 2 cases per year. Further, lung cancer often emerges on a background of chronic respiratory disease and symptoms of chronic cough—typically in patients who smoke. It can be very difficult to identify changes in these chronic symptoms that might indicate the development of a lung tumour.

Smoking remains the principal aetiological factor and smoking cessation is the key public health initiative to reduce mortality from this disease; 9 indeed, at almost any age smoking cessation can produce health benefits. Hence, public health campaigns to promote smoking cessation, supplemented by strategies in primary care based on nicotine replacement therapies should be encouraged. 10 The role of e-cigarettes is not yet fully understood, 11 although any strategy that reduces exposure to tobacco smoke has a potential for producing significant benefits.

How do patients respond to lung cancer symptoms?

There is a significant body of research around patient response to symptoms that might potentially indicate lung cancer. Because symptoms often present within the context of chronic respiratory symptomatology, changes associated with the development of a tumour may go un-noticed or be dismissed. 8 It is known that patients often delay their help seeking through a range of psychological mechanisms including denial and nihilism—hence, there can often be significant delays before patients present to primary care. 12 , 13

There is evidence for variation in the timeliness of presentation of lung cancer in between countries; people with lung cancer often have symptoms for a considerable period of time before they present to primary care and this is a major source of delay in the diagnostic process with potential adverse impact on survival; 14 , 15 this patient interval does, however, vary between studies. It is important that PCPs understand some of the psychological mechanisms that either promote or inhibit early presentation among their patients.

Public awareness of lung cancer

Over the past few years, there have been campaigns run throughout the UK designed to make the public more aware of symptoms associated with lung cancer—for example the ‘Be clear on Cancer’ campaign run by Public Health England and ‘Diagnose Cancer Early’ in Scotland 16 , 17 (see Fig. ​ Fig.1). 1 ). These campaigns have demonstrated an ability to diagnose additional cancers and effect modest increases in the proportion of patients having tumours diagnosed at stages where they are amenable to resection. 18 , 19

Posters used in the ‘Be Clear on Cancer’ campaign

Of course, lung cancer early detection programmes need to be focussed on the hard-to-reach population and those who will benefit most from involvement; there are often concerns expressed over burdening services with patients with insignificant symptoms 18 and an emerging consensus that all stakeholders should be closely engaged in the campaigns. Nevertheless, available evidence suggests that lung cancer could be diagnosed earlier through these public awareness campaigns, 19 particularly when associated with systems to help primary care physicians risk stratify their patients for lung cancer more effectively—indeed, further work to identify patients who might benefit from targeted interventions should be a priority.

Community-based social marketing interventions have a potential key role; 20 they can increase the likelihood of patients attending PCPs and increase primary care diagnostic activity (such as chest X-ray referrals)—as well as increases in lung cancer diagnostic rates. The level of suspicion at which PCPs consider a referral is a key factor in response to these campaigns—and there are concerns over ‘system overload’ through encouragement to present with symptoms. 13 Ideally, campaigns might preferentially target those at greater risk of lung cancer, such as people with significant smoking histories or occupational exposure.

Primary care response to lung cancer symptoms

In the UK, GPs will on average only diagnose one or two cases of lung cancer per year (if they are in full-time practice). 21 However, during that year, GPs will see hundreds of patients with common symptoms, such as cough, breathlessness and chest pain—hence, there are significant difficulties in identifying, diagnosing and referring these patients in a timely manner.

The 2015 NICE lung cancer guidelines on recognition and referral 22 have underpinned some important strategies to enhance timely lung cancer diagnosis; in many regions of the UK, there are now accelerated diagnostic pathways that assist GPs in identifying and referring patients appropriately. 23 Audit data demonstrate that there are typically several consultations prior to a diagnosis of lung cancer being made. 24 Evidence from significant event analysis in the UK has suggested that there is timely recognition and referral of symptoms in primary care; 25 longer intervals are typically attributed to factors such as X-rays being reported as normal, patient-mediated factors and presentations complicated by co-morbidity. The importance of safety netting has also been emphasised in presentations where a diagnosis of lung cancer is possible. 26

There needs to be continued work to counteract the ‘nihilism’ associated with lung cancer; PCPs are very well aware of patients who may suspect they have lung cancer but fail to present either because they blame themselves (through a history of smoking) or because they believe that if a cancer is diagnosed there is little that can be done about it. 27 This, coupled with the tendency for patients in the UK to be concerned about ‘bothering the doctor’, 28 can have detrimental effects on early diagnosis.

While public campaigns can do much to overcome barriers to presentation, it is vital that PCPs become more pro-active in achieving more timely diagnosis in their practice populations. It is been recommended that they should recognise the psychological mechanisms that might underlie patient delay and tackle nihilistic attitudes through educational and motivational strategies. 29 Indeed, there is cause for cautious optimism with new treatments, and this should be conveyed to patients; for example, the use of stereotactic radiotherapy and volume-sparing surgery means that patients who previously could not be offered curative treatment due to co-morbidities are often now eligible. 30

Audits that systematically identify at-risk patients who may be failing to present are a potential way forward; interventions which identify and target high-risk patients appear feasible in primary care. 31 Crucially, patients should be reassured that PCPs are always happy to see them if they are worried about potential cancer symptoms.

Risk assessment and lung cancer

It is vital in assessing lung cancer risk to look carefully at lifestyle factors and past medical history; only one in seven cases of lung cancer occur in people who have never smoked, and the presence of chronic obstructive pulmonary disease doubles the risk independent of smoking history. 32 A previous history of head and neck, bladder and renal cancers and other factors such as exposure to asbestos or living in high radon exposure areas are all important in lung cancer risk assessment. Family history produces an excess of risk and should be included in risk assessment—as should the symptom of fatigue, a common feature of lung cancer. Cancer decision support tools such as the ‘Caper’ instrument or ‘Q cancer’ have emerged in recent years in the UK, enabling GPs to make assessments of cancer risk based on presenting symptoms; 33 , 34 they have been incorporated into clinical systems in primary care with mixed results.

Beyond these symptom-based models, a number of lung cancer risk models have been developed based on validated epidemiological criteria—for example, the Liverpool Lung Project (LLP) risk model 35 ( www.MyLungRisk.org ), which was subsequently used in the UK Lung Cancer Screening Trial. 36 The LLP v2 risk model has also been used in the Liverpool Healthy Lung project, 37 which has accommodated the risk model within primary care practice and produced risk assessments that are useful in clinical decision making is now running into its third year. The Manchester lung cancer pilot study 38 has used the PLCO 2012 risk prediction model 39 and the recent Yorkshire Lung cancer screening trial 40 is using both the LLP v2 and the PLCO 2012 risk models. Models such as these provide a systematic way of assessing lung cancer risk, taking into account a range of factors, including smoking duration, previous respiratory disease, family history of lung cancer, age, previous history of malignancy and asbestos exposure.

Risk stratification in primary care is clearly a key priority. We need to look at instruments such as the LLP model and identify ways that lung cancer risk stratification can be made easy and convenient in primary care. At present, it is not possible to recommend a specific risk assessment tool for use in primary care; current ongoing research in primary care is externally validating existing tools and will compare their efficacy. 41 Acceptability and feasibility also need to be examined; complex algorithms that place extra burden on practitioners are unlikely to succeed. However, we do need to ensure that the basic risk prediction parameters are correctly documented in primary care, so they can be utilised in any future national lung cancer screening programme approved by the UKNSC. We also need a better understanding of ways to maximise benefits of these models—while minimising potential harms such as over-medicalisation, anxiety and false reassurance. 42 Machine learning or neuro-linguistic programming, whereby data from multiple practice-based and external sources might be examined to develop risk estimates, are also likely to play a significant role in the future. 43

Diagnostic pathways

Early diagnosis lung cancer clinics based on multi-disciplinary teams (MDTs) are an ideal option for expediting diagnosis—ideally with an urgent (2-week wait) referral; 44 there is good evidence that these specialist MDT clinics are associated with improved outcomes. Another important consideration is involving the whole primary care team and including other practitioners such as pharmacists who see a lot of patients with, for example, repeat purchases of cough medicine. There has been a push to change referral practices in some parts of the UK—for example, to lower the threshold that PCPs refer for chest X-ray 45 and to encourage practitioners to repeat the investigation after a few months if symptoms persist; critically a normal chest X-ray does not exclude diagnosis of lung cancer. One highly successful programme in Leeds included the option for people to self-refer for chest X-rays in walk-in clinics 19 —a crucial element was the engagement of primary care in the design and implementation of the programme.

Diagnostic pathways have been closely examined and tested over recent years, an example being CRUK’s ACE programme (accelerate, coordinate and evaluate) initiated in June 2014 in England and Wales. 23 Patients often have complex pathways that can lead to delays; important initiatives in the ACE programme and elsewhere include risk-stratified computed tomographic (CT) screening criteria for ‘straight to CT’ referrals following normal chest X-rays and a focus on diagnostic paths for patients with vague symptoms.

Work needs to continue on diagnostic pathways that might expedite lung cancer diagnosis. It is important, for example, that we get more evidence on the impact or potential impact of direct access to investigations such as spiral CT from primary care—at present, there is not sufficient evidence or resource to universally implement this strategy, and there is evidence that delays can occur in primary care (for example, through ordering too many chest X-rays. 46 Nevertheless, GPs in the UK often indicate that direct access to investigations would help streamline diagnosis. 7

Lung cancer screening

A major challenge for primary care is the lack of symptoms in very early stage lung cancer, highlighting the importance of examining the potential of screening. The US National Lung Cancer Screening Trial, which used low-dose CT scanning in high-risk patients, showed a 20% reduction in lung cancer-specific mortality and almost a 7% reduction in all-cause mortality—and the US Preventive Task Force on Lung cancer Screening recommended that lung cancer screening should be implemented in high-risk populations. 47 , 48 Accordingly, Medicare agreed to pay for lung cancer screening within certain criteria—however, the current uptake in the US is only ~2% of high-risk individuals.

The recent report on the NELSON trial at the World Lung Cancer Conference, Toronto 49 has demonstrated an encouragingly low rate of false positives and a mortality benefit of 26% in men and between 39% and 61% in women—depending on the number of years of follow-up (i.e. 8–10 years). These results provide further impetus for the introduction of spiral CT scanning for individuals at high risk of cancer in the UK. Figure ​ Figure2 2 illustrates the process for identifying an appropriate screening population, recruiting them and implementing screening—in many ways more complex than existing cancer screening programmes where recruitment is based principally on age and gender.

Levels of evidence for the implementation of lung cancer screening in Europe. The colour codes refer to the current status March 2019; traffic lights: green—ready, amber—borderline evidence. Underlined text indicates particular relevance for primary care 53

If we are, indeed, on the cusp of a new screening programme, there are important implications for primary care; the key issue in lung cancer screening is identifying the right patients to invite. This is a task that would involve primary care which currently lacks the systems and the processes to undertake the kind of population- based lung cancer risk assessment required. It is important, therefore, that we plan for an era where high-risk patients are screened for lung cancer (implemented, ideally, in tandem with smoking cessation programmes). We should be refining current strategies to risk stratify patients in primary care in preparation for this new era. 50 , 51 Screening alone, however, is not the total answer and a high level of awareness in both the public and the primary care community will remain vital elements in what needs to be a multi-pronged approach. 52

Conclusions and recommendations

Mortality rates for lung cancer remain stubbornly high; if we are to improve lung cancer outcomes, it is important that early diagnosis and screening efforts achieve their maximum potential. We need to:

• identify ways of raising awareness of symptoms potentially associated with lung cancer in ways that encourage people at higher risk to come forward—this will require refinement of the messages delivered in awareness-raising strategies
• counter the nihilistic beliefs often associated with lung cancer—early diagnosis CAN lead to improved outcomes
• continually strive to improve the primary care response to patients with symptoms of lung cancer, supported by better diagnostic pathways and risk-based decision support
• identify ‘fail-safe’ mechanisms by which patients advised to ‘watch and wait’ are not lost to follow-up; it is vital that patients understand these safety netting and follow-up advice
• ensure that the basic risk prediction parameters are correctly documented in primary care, so they can be utilised in any future national lung cancer screening programme approved by the UKNSC
• refine methods to implement lung cancer risk assessment model approaches; this is key to improving diagnosis of early lung cancer—and we should aim for risk estimates that can be readily incorporated into the various kinds of practice software used in primary care practices
• continue to improve diagnostic pathways; at present, many different models are being evaluated, including those which give primary care more direct access to investigations such as spiral CT. The key task will be implementation and appropriate support once the best models are determined
• fully engage primary care with the likely implementation of spiral CT lung cancer screening in the next few years—this will require the best possible risk-stratification approaches to ensure screening is directed at those who stand to benefit the most from it. It is vital that primary care rises to this challenge

Primary care needs to play a central role in efforts to diagnose lung cancer earlier, if there is to be an improvement in lung cancer outcomes in the years ahead. Research over the past decade gives us a much clearer idea of what needs to be done in refining primary care-based strategies; with adequate commitment and resources primary care will, in conjunction with other health care sectors, help reduce the burden from this disease.

Author contributions

D.P.W. led on literature searching and draft manuscript preparation. J.K.F. and M.D.P. provided input to early drafts and added text in their areas of expertise.

Competing interests

The authors declare no competing interests.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Small Cell Lung Cancer (SCLC) Clinical Presentation

• Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
• Sections Small Cell Lung Cancer (SCLC)
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Complications
• Approach Considerations
• Routine Laboratory Studies
• Thoracic Imaging Studies
• Brain and Spinal Cord Imaging Studies
• Skeletal Radionuclide Imaging
• PET Scanning
• Bronchoscopy and Fine Needle Aspiration
• Sputum Cytology
• Thoracentesis
• Histologic Findings
• Staging Overview
• VALSG and TNM Staging
• Combination Chemotherapy
• Chemotherapy Dose Intensity and Density
• Limited-Stage SCLC - Standard Management
• Extensive-Stage SCLC - Standard Management
• Management of Relapsed SCLC
• Management of Brain Metastases and Spinal Cord Compression
• Surgical Resection
• Management of Complications
• Consultations
• Long-Term Monitoring
• Guidelines Summary
• Treatment for Limited-Stage SCLC
• Treatment for Extensive-Stage SCLC
• Treatment of SCLC in the Elderly
• Medication Summary
• Antineoplastics, Alkylating
• Topoisomerase Inhibitors
• Antineoplastics, Anthracycline
• Antineoplastics, Vinca Alkaloid
• Antineoplastics, Antimicrotubular
• Antineoplastics, Antimetabolite
• Antineoplastics, Podophyllotoxin Derivatives
• Bispecific T-Cell Engager (BiTE) Antibodies
• PD-1/PD-L1 Inhibitors
• Corticosteroids
• Antiemetic Agents
• Questions & Answers
• Media Gallery

Fewer than 5% of patients with small cell lung cancer (SCLC) are asymptomatic at presentation. Common presenting signs and symptoms of the disease, which very often occur in advanced-stage disease, include the following:

• Shortness of breath
• Weight loss
• Neurologic dysfunction

Most patients with this disease present with a short duration of symptoms, usually only 8-12 weeks before presentation. The clinical manifestations of SCLC can result from local tumor growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes.

Local tumor growth

SCLCs are usually centrally located and may cause irritation and/or obstruction of the major airways. Common symptoms resulting from local tumor growth include cough, dyspnea, and hemoptysis. Squamous cell cancer also presents as a central lesion, but unlike SCLC, it frequently exhibits central cavitation.

Rapid tumor growth may lead to obstruction of major airways, with distal collapse leading to postobstructive pneumonitis, infection, and fever.

Intrathoracic spread

SCLCs usually grow rapidly and metastasize to mediastinal lymph nodes relatively early in the course of the disease. At presentation, patients may have very large intrathoracic tumors, and distinguishing the primary tumor from lymph node metastases may be impossible.

Pressure on mediastinal structures can cause various symptoms, including the following:

• Superior vena cava (SVC) obstruction
• Hoarseness - Due to compression of the recurrent laryngeal nerve
• Hemi-diaphragm paralysis - Due to phrenic nerve compression
• Dysphagia - Due to esophageal compression
• Stridor - Due to compression of the major airways

SCLC causes SVC obstruction more often than non-SCLC (NSCLC) . Patients present with swelling of the face and upper extremities, and can develop stridor due to laryngeal edema or headache, dizziness, and other neurologic symptoms due to cerebral edema. Hoarseness of recent onset can be caused by compression of the left recurrent laryngeal nerve by a mediastinal mass involving the aortopulmonary window (ie, primary tumor or lymph node metastasis).

Compression of the phrenic nerve causes paralysis of the ipsilateral hemidiaphragm, contributing to shortness of breath. In addition, esophageal compression can lead to dysphagia and odynophagia, and compression of the mainstem bronchi and trachea can cause severe shortness of breath and stridor or wheezing.

Symptoms from distant spread

Common sites of hematogenous metastases include the brain, bones, liver, adrenal glands, and bone marrow. The symptoms depend upon the site of spread.

Neurologic dysfunction can occur due to brain metastases or spinal cord compression. Patients with symptomatic brain metastases may have raised intracranial pressure secondary to mass lesions and vasogenic edema. Common symptoms include the following:

• Headache - Usually worse in the morning
• Blurred vision
• Photophobia
• Slurred speech
• Localizing symptoms - Such as extremity weakness

Suspected spinal cord compression is an oncologic emergency. Early recognition of vertebral and paraspinal metastases is important, because a delay in diagnosis and treatment frequently results in permanent loss of neurologic function. The initial symptom is usually back pain, with or without neurologic dysfunction. Once present, neurologic dysfunction can progress very rapidly (ie, within hours) to cause quadriplegia or paraplegia, depending upon the location of the lesion.

Other symptoms from distant metastasis may include pain from bone metastasis, as well as jaundice or abdominal/right upper quadrant pain due to liver metastasis.

Paraneoplastic syndromes

Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm or ectopic production of a hormone or cytokine. Table 1, below, shows some examples of the paraneoplastic syndromes affecting the endocrine and neurologic systems in patients with SCLC.

See  Paraneoplastic Diseases for more information.

Table 1. Paraneoplastic Syndromes Affecting Endocrine and Neurologic Function in SCLC (Open Table in a new window)

Physical findings in small cell lung cancer (SCLC) depend upon the extent of local and distant spread and the organ system involved.

Respiratory system

Patients usually experience shortness of breath; physical examination may reveal use of the accessory muscles of respiration (scalene muscles, intercostal muscles) and flaring of the nasal alae. In addition, by virtue of a central tumor location, patients may develop distal atelectasis and postobstructive pneumonia. With pleural effusion , the examination reveals dullness to percussion and decreased or absent breath sounds on the side of the effusion.

Cardiovascular system

Pericardial effusions may be asymptomatic when small, or they may result in tamponade if they are large or accumulate over a short period. Patients are usually short of breath and their heart sounds may be distant on auscultation. Jugular venous pulsation is elevated, and, paradoxically, it rises with inspiration.

Tamponade is an emergency and requires immediate decompression of the pericardium. Pulsus paradoxus is a classic sign of pericardial tamponade . If tamponade is suspected, an echocardiogram should be performed. The definitive diagnosis is established with cardiac catheterization, which reveals equalization of pressures in cardiac chambers. Definitive management may include chemotherapy and/or surgical creation of a pleuropericardial window.

Examination of the extremities may reveal clubbing, cyanosis, or edema. In the presence of superior vena cava (SVC) obstruction, the right upper extremity is usually edematous.

Central nervous system

Asymptomatic brain metastases occur in 5-10% of patients with SCLC (see Workup). Patients with symptomatic brain metastases may have raised intracranial pressure secondary to mass lesions and surrounding brain edema. The physical findings depend on the site of the brain lesions.

Perform funduscopy to look for signs of raised intracranial pressure, as well as a thorough neurologic examination and an evaluation of cerebellar function, coordination, and gait.

Gastrointestinal system

The liver is a common site of metastatic spread. Physical examination may reveal icterus (secondary to widespread liver metastasis or obstruction of biliary outflow) and/or hepatomegaly. However, most patients do not have any specific finding related to the gastrointestinal (GI) tract on examination. Very often patients are asymptomatic but may have mild elevation of liver enzyme levels.

Lymphatic system

Carefully perform a lymph node examination. Currently, enlarged ipsilateral supraclavicular lymph nodes are included in limited-stage disease, but enlarged axillary lymph nodes upstage the diagnosis to extensive-stage disease.

Multiple complications may be noted, depending on the site of metastasis or the metabolic factor that the tumor affects. Hypercalcemia could initially be asymptomatic but in late stages could lead to weakness, fatigue, and sleepiness, and in extreme cases to severe constipation and lethargy.

Brain metastasis is often asymptomatic but could manifest as a unilateral eye abnormality, focal neurologic deficit, or at times with a new-onset headache that wakes the patient up. Seizures are a possible manifestation.

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Heigener D, Freitag L, Eschbach C et al. Topotecan/cisplatin (TP) compared to cisplatin/etoposide (PE) for patients with extensive disease-small cell lung cancer (ED-SCLC): final results of a randomised phase III trial. J Clin Oncol. 2008;26 (suppl):400s.

Slotman BJ, van Tinteren H, Praag JO, Knegjens JL, El Sharouni SY, Hatton M, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet . 2015 Jan 3. 385 (9962):36-42. [QxMD MEDLINE Link] . [Full Text] .

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• High-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the image.
• This coronal positron emission tomogram shows a large, focal, hypermetabolic area on the right that is consistent with a large mass in the central portion of the right upper pulmonary lobe. Multiple other smaller hypermetabolic areas suggest lymph-node metastatic disease in the chest, abdomen, and right supraclavicular region.
• Table 1. Paraneoplastic Syndromes Affecting Endocrine and Neurologic Function in SCLC
• Table 2. AJCC TNM Categories for Lung Cancer
• Table 3. AJCC Stage Groupings for Lung Cancer

Contributor Information and Disclosures

Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman, Division of Hematology/Oncology Education, Chair, Cancer Survivorship Program, Associate Chair, Department of Medicine Faculty Development, Mayo Clinic Florida; Vice President, Florida Society of Clinical Oncology Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians , American Society of Clinical Oncology , American Society of Hematology , Philippine Medical Association , Texas Medical Association Disclosure: Nothing to disclose.

Irfan Maghfoor, MD Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia Irfan Maghfoor, MD is a member of the following medical societies: American Society of Hematology Disclosure: Nothing to disclose.

Nagla Abdel Karim, MD, PhD Director of Early Therapeutics, Inova Schar Cancer Institute; Professor of Medicine, University of Virginia School of Medicine Nagla Abdel Karim, MD, PhD is a member of the following medical societies: American Medical Association , American Society of Clinical Oncology , Egyptian American Medical Association, Egyptian Cancer Society, International Association for the Study of Lung Cancer Disclosure: Nothing to disclose.

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• Small Cell Lung Cancer Staging
• Non-Small Cell Lung Cancer (NSCLC) Staging
• Small Cell Lung Cancer (SCLC)
• Small Cell Lung Cancer (SCLC) Imaging
• Non-Small Cell Lung Cancer (NSCLC)
• Non-Small Cell Lung Cancer (NSCLC) Imaging
• Genetics of Non-Small Cell Lung Cancer
• FDA Approves Tarlatamab for Extensive-Stage Small Cell Lung Cancer
• IASLC Issues Consensus on Neoadjuvant, Adjuvant Treatments in Non–Small Cell Lung Cancer
• Is Consolidation Osimertinib Superior to Durvalumab in EGFR-Mutated Non–Small Cell Lung Cancer?

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Patritumab deruxtecan demonstrated statistically significant improvement in progression-free survival versus doublet chemotherapy in patients with locally advanced or metastatic egfr-mutated non-small cell lung cancer in herthena-lung02 phase 3 trial.

September 17, 2024 6:00 am ET

Daiichi Sankyo and Merck’s patritumab deruxtecan demonstrates a statistically significant progression-free survival improvement in this EGFR-mutated non-small cell lung cancer population with high unmet need following prior EGFR TKI treatment

Discussions with global regulatory authorities to be initiated

BASKING RIDGE, N.J. & RAHWAY, N.J., September 17, 2024 – The HERTHENA-Lung02 phase 3 trial evaluating patritumab deruxtecan in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who received prior EGFR tyrosine kinase inhibitor (TKI) treatment met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement versus platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy. Overall survival (OS) data were immature at the time of the analysis and the trial will continue to further assess OS, a secondary endpoint.

Patritumab deruxtecan is a specifically engineered potential first-in-class HER3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and Merck (NYSE: MRK), known as MSD outside of the United States and Canada.

NSCLC accounts for approximately 85% of all lung cancers worldwide with up to 70% of NSCLC cases diagnosed at an advanced stage and EGFR-activating mutations occur in 14% to 38% of all NSCLC tumors worldwide. 1,2,3 Following initial treatment for metastatic EGFR-mutated NSCLC with an EGFR TKI, many patients experience disease progression and currently available therapies in the second-line setting are limited, highlighting the need for new approaches to improve outcomes. 3,4

Data from the HERTHENA-Lung02 trial will be presented at an upcoming medical meeting and shared with global regulatory authorities.

“These results from HERTHENA-Lung02 demonstrate the potential of patritumab deruxtecan to become an important treatment option for certain patients with EGFR-mutated non-small cell lung cancer with prior tyrosine kinase inhibitor treatment,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “We plan to share these findings with regulatory authorities to discuss next steps.”

“We are encouraged by these results demonstrating a statistically significant progression-free survival improvement compared to platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer who received prior tyrosine kinase inhibitor treatment,” said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck. “Together with Daiichi Sankyo, we are committed to helping patients with previously treated EGFR-mutated non-small cell lung cancer, where there is a high unmet need.”

The safety profile seen in HERTHENA-Lung02 was consistent with that observed for patritumab deruxtecan in previous lung cancer clinical trials with no new safety signals identified. The majority of interstitial lung disease (ILD) events were low grade (grade 1 and 2). There were two grade 5 ILD events observed.

About HERTHENA-Lung02

HERTHENA-Lung02 is a global, multicenter, open-label, phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan (5.6 mg/kg every three weeks) versus four cycles of pemetrexed and platinum chemotherapy in patients with metastatic or locally advanced NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) after failure of third-generation (e.g., osimertinib, lazertinib, aumolertinib, alflutinib) EGFR TKI therapy. Patients in the comparator arm without disease progression after four cycles of pemetrexed and platinum chemotherapy are able to continue treatment with maintenance pemetrexed with no restriction on the number of cycles.

The primary endpoint of HERTHENA-Lung02 was PFS as assessed by blinded independent central review (BICR). Secondary endpoints included OS, objective response rate, duration of response, clinical benefit rate, time to response, disease control rate, and safety. Patients enrolled in the study underwent brain imaging to allow for assessment of intracranial endpoints, including intracranial PFS as assessed by BICR.

HERTHENA-Lung02 enrolled 586 patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov .

About EGFR-Mutated Non-Small Cell Lung Cancer

Nearly 2.5 million lung cancer cases were diagnosed globally in 2022. 5 Lung cancer is the most common cancer and the leading cause of cancer-related deaths worldwide. 5 Approximately 85% of lung cancer is classified as NSCLC with EGFR-activating mutations occurring in 14 to 38% of all NSCLC tumors worldwide. 1,3 NSCLC is diagnosed at an advanced stage in up to 70% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy. 2,6

Following initial treatment for metastatic EGFR-mutated NSCLC with an EGFR TKI, many patients experience disease progression and currently available therapies in the second-line setting are limited, highlighting the need for new approaches to improve outcomes. 3,4

HER3 is a member of the HER family of receptor tyrosine kinases. 7 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment. 8 HER3 is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival. 9,10 There is currently no HER3 directed therapy approved for the treatment of any cancer.

About Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other therapies in a global development program, which includes HERTHENA-Lung02 , a phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan versus pemetrexed plus platinum chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression on or after treatment with a third-generation EGFR TKI; HERTHENA-Lung01 , a phase 2 trial in metastatic or locally advanced NSCLC with an activating EGFR mutation previously treated with at least one EGFR TKI and one platinum-based chemotherapy-containing regimen; HERTHENA-PanTumor01 , a phase 2 trial in 10 locally advanced or metastatic solid tumor types, including melanoma, gastric and head and neck cancer, among other types of cancer, previously treated with at least one prior systemic therapy; a phase 1 trial in combination with osimertinib in EGFR-mutated locally advanced or metastatic NSCLC; and a phase 1 trial in previously treated patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing metastatic breast cancer also has been completed.

About the Daiichi Sankyo and Merck Collaboration

Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. In August 2024 , the global co-development and co-commercialization agreement was expanded to include MK-6070 which they will jointly develop and commercialize worldwide, except in Japan where Merck will maintain exclusive rights. Merck will be solely responsible for manufacturing and supply for MK-6070.

About the ADC Portfolio of Daiichi Sankyo

The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. 

The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo   

Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit www.daiichisankyo.com . 

Merck’s Focus on Cancer

Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit  https://www.merck.com/research/oncology/ . 

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . 

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This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. 

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. 

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). 

________________________________

1 Economopoulou P, et al.  Ann Transl Med . 2018; 6(8):138.

2 Guo H, et al. Front Oncol . 2021; 11: 761042.

3 Pretelli G, et al. Int J Mol Sci . 2023; 24, 8878.

4 Janne PA, et al.  Cancer Discov . 2022; 12(1):74-89.

5 World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet . Accessed July 2024.

6 Hardstock F, et al. BMC Cancer . 2020; 20(1):260.

7 Mishra R, et al. Onco Rev . 2018; 12(355):45-62.

8 Scharpenseel H, et al. Scientific Reports . 2019; 9:7406.

9 Gandullo-Sánchez L et al.  J Exp Clin Cancer Res .  2022; 41:310.

10 Yu H.A., et al. Annals of Oncology . 2024; 35(5): P437-447.

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Forward-looking statement of Merck & Co., Inc., Rahway, N.J., USA

This website of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov). No Duty to Update The information contained in this website was current as of the date presented. The company assumes no duty to update the information to reflect subsequent developments. Consequently, the company will not update the information contained in the website and investors should not rely upon the information as current or accurate after the presentation date.

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Subgroup Analysis from Pivotal WU-KONG1B Study Exhibits Robust Efficacy of Sunvozertinib in Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations Across Different Baseline Characteristics

Results of subgroup analysis from the pivotal WU-KONG1B study in relapsed or refractory NSCLC with EGFR exon20ins presented at ESMO 2024

• Sunvozertinib demonstrated promising anti-tumor efficacy, regardless of EGFR exon20ins region classification, race, region, baseline brain metastasis, prior amivantamab or prior immunotherapy status.
• The safety profile of sunvozertinib was similar to previously reported results, and clinically manageable.

SHANGHAI , Sept. 17, 2024 /PRNewswire/ -- Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, presented subgroup analysis findings of its WU-KONG1 Part B (WU-KONG1B) study at the 2024 European Society for Medical Oncology (ESMO) Congress. The results showed promising anti-tumor efficacy of sunvozertinib in relapsed or refractory non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins) across different baseline characteristics, underpinning its significant clinical value for this patient population around the globe.

WU-KONG1B is an open-label, multinational pivotal study to investigate the efficacy and safety of sunvozertinib in relapsed or refractory NSCLC with EGFR exon20ins. The study is currently being conducted across 10 countries and regions in Asia , Europe , North America , and South America . WU-KONG1B met its primary endpoint, with the preliminary results featured as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrating the transformative potential of sunvozertinib as a single, oral agent to treat EGFR exon20ins NSCLC. Results of the subgroup analysis were presented on September 14 at the 2024 ESMO Congress in Barcelona, Spain .

As of March 22, 2024 , a total of 107 patients with at least 33 EGFR exon20ins subtypes were included in the efficacy analysis set. The key findings were as follows:

• Per independent review committee (IRC) assessment, target lesions shrinkage was observed in 92.4% (98/106) of patients.
• By EGFR exon20ins region classification, the best ORR in near loop, far loop, C-helix and unknown were 51.9%, 59.1%, 66.7% and 40%, respectively.
• IRC assessed ORR was comparable between different subgroups regardless of race, region, baseline disease characteristics and prior anti-cancer treatment history.

• With median follow-up of 7 months, duration of response (DoR) was not reached, and 66.7% of responders were still responding.
• The safety profile was similar to previously reported results, and clinically manageable.

“WU-KONG1B study enrolled more than 40% of non-Asian patients. The subgroup analysis suggested superior anti-tumor efficacies and well-tolerated safety profiles of sunvozertinib across EGFR exon20ins NSCLC patients with different baseline demographics and clinical characteristics on a global scale. We are intensifying our efforts to advance ongoing global pivotal studies and regulatory submissions of this FDA Breakthrough Therapy Designated asset, making available an effective and safe oral option to more patients around the world.” said Xiaolin Zhang , PhD, CEO of Dizal.

WU-KONG28, a phase Ⅲ multinational randomized study, is ongoing to assess sunvozertinib versus platinum-based doublet chemotherapy as a first-line treatment in patients from 16 countries and regions in Asia , Europe , North America , and South America . The anticipated data of this study is expected to further improve outcomes of patients in this realm.

About s unvozertinib (DZD9008)

Sunvozertinib is an irreversible EGFR inhibitor discovered by Dizal scientists targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023 , sunvozertinib received approval from NMPA to treat advanced NSCLC with EGFR exon20ins after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins. The primary endpoint of the study was the confirmed overall response rate (cORR) as assessed by the Independent Review Committee (IRC) reached 60.8%. Anti-tumor efficacy was observed across a broad range of EGFR exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M, and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug-related TEAEs (treatment-emergent adverse event) were Grade 1/2 in nature and clinically manageable.

Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 Part B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR exon20ins.

Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery (IF:39.397) and The Lancet Respiratory Medicine (IF: 76.2).

About Dizal

Dizal is a biopharmaceutical company, dedicated to the discovery, development and commercialization of differentiated therapeutics for the treatment of cancer and immunological diseases. The company aims to develop first-in-class and groundbreaking new medicines, and further address unmet medical needs worldwide. Deep-rooted in translational science and molecular design, it has established an internationally competitive portfolio with two leading assets in global pivotal studies, both of which have already been launched in China.

To learn more about Dizal, please visit www.dizalpharma.com , or follow us on Linkedin or Twitter .

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These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections, and understandings of the management of Dizal with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties, and other factors, some of which are beyond Dizal’s control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, Dizal’s competitive environment, and political, economic, legal, and social conditions.

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Predicting the T790M mutation in non-small cell lung cancer (NSCLC) using brain metastasis MR radiomics: a study with an imbalanced dataset

• Open access
• Published: 14 September 2024
• Volume 15 , article number  447 , ( 2024 )

Cite this article

You have full access to this open access article

• Wen-Feng Wu 1 ,
• Kuan-Ming Lai 1 , 2 ,
• Chia-Hung Chen 1 , 2 ,
• Bai-Chuan Wang 3 ,
• Yi-Jen Chen 3 ,
• Chia-Wei Shen 3 ,
• Kai-Yan Chen 3 ,
• Eugene C. Lin 3 , 4 &
• Chien-Chin Chen 5 , 6 , 7 , 8  

Early detection of T790M mutation in exon 20 of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients with brain metastasis is crucial for optimizing treatment strategies. In this study, we developed radiomics models to distinguish NSCLC patients with T790M-positive mutations from those with T790M-negative mutations using multisequence MR images of brain metastasis despite an imbalanced dataset. Various resampling techniques and classifiers were employed to identify the most effective strategy.

Radiomic analyses were conducted on a dataset comprising 125 patients, consisting of 18 with EGFR T790M-positive mutations and 107 with T790M-negative mutations. Seventeen first- and second-order statistical features were selected from CET1WI, T2WI, T2FLAIR, and DWI images. Four classifiers (logistic regression, support vector machine, random forest [RF], and extreme gradient boosting [XGBoost]) were evaluated under 13 different resampling conditions.

The area under the curve (AUC) value achieved was 0.89, using the SVM-SMOTE oversampling method in combination with the XGBoost classifier. This performance was measured against the AUC reported in the literature, serving as an upper-bound reference. Additionally, comparable results were observed with other oversampling methods paired with RF or XGBoost classifiers.

Conclusions

Our study demonstrates that, even when dealing with an imbalanced EGFR T790M dataset, reasonable predictive outcomes can be achieved by employing an appropriate combination of resampling techniques and classifiers. This approach has significant potential for enhancing T790M mutation detection in NSCLC patients with brain metastasis.

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1 Introduction

Patients diagnosed with lung cancer and concomitant brain metastasis often face a grim prognosis. The incidence of brain metastasis in lung cancer patients at the time of initial presentation is alarmingly high, ranging from 77 to 88%, according to population-based studies [ 1 ]. In the case of non-small cell lung cancer (NSCLC) patients, a spectrum of therapeutic strategies has been devised to manage intracranial disease, encompassing both localized and systemic interventions. However, it is essential to acknowledge that localized treatments alone, such as neurosurgery and radiation therapy, may not uniformly improve the clinical outlook for every afflicted patient [ 2 ]. Conversely, systemic therapeutic options comprise chemotherapy, targeted therapy, and immunotherapy, with targeted therapy being particularly relevant for individuals harboring epidermal growth factor receptor (EGFR) mutations [ 3 , 4 , 5 ]. EGFR mutations are detected in 7% to 76% of NSCLC patients, with a notably higher prevalence in the Asia–Pacific region [ 6 ]. These mutations primarily manifest as activating alterations within the EGFR intracellular kinase domain, mainly occurring at exons 18 to 21. These genetic events set off downstream signaling pathways that potentiate NSCLC tumorigenesis [ 7 ]. The frequency of EGFR kinase domain mutations in NSCLC includes 5% for nucleotide substitutions in exon 18, 45% for in-frame deletions in exon 19, 5% for in-frame insertions in exon 20, and 40–45% for L858R substitutions in exon 21 [ 7 ].

Studies have unequivocally demonstrated that the development and utilization of tyrosine kinase inhibitors (TKIs) across three generations have significantly enhanced progression-free survival (PFS) in treatment-naive patients with EGFR-mutated advanced NSCLC [ 4 ], subsequently translating into improved overall survival (OS) for those with stage IV EGFR mutation-positive NSCLC [ 5 ]. First and second-generation EGFR-TKIs have become the gold standard for first-line treatment in EGFR mutation-sensitive NSCLC patients (exon 19 deletion or L858R substitution), consistently yielding response rates ranging from 56% to a remarkable 84.6%, nearly doubling the efficacy observed with conventional chemotherapy [ 8 ]. Nevertheless, resistance to first-line EGFR-TKIs has been documented, often mediated by the emergence of the T790M mutation [ 8 ]. The T790M mutation, characterized by the substitution of threonine with methionine at residue 790 [ 8 , 9 , 10 ], has demonstrated a strong association with the development of brain metastasis in patients with EGFR mutations undergoing first- or second-generation EGFR-TKI therapy [ 11 ]. The advent of osimertinib, a third-generation EGFR-TKI, has proven to be a game-changer, improving median PFS in T790M-positive NSCLC patients [ 12 , 13 ]. Consequently, in clinical practice, it becomes imperative to ascertain EGFR mutation status and promptly detect the presence of the T790M mutation, particularly during disease progression, utilizing a non-invasive methodology to make informed decisions regarding EGFR-TKI therapy or combination treatments.

While previous research has predominantly concentrated on utilizing radiomics derived from chest CT [ 14 , 15 , 16 ], lung PET/CT [ 17 , 18 ], or chest MR [ 19 ] images to predict EGFR mutation status in lung cancer, there has been a recent expansion of this approach to investigate EGFR mutation status in brain metastases of lung cancer patients through radiomic analyses [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. These studies have employed various feature selection methods and classification algorithms to construct predictive models. The discrepancy of EGFR expression or mutation status between brain metastases and the matched primary NSCLC [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ] implies the need to select brain metastases rather than their corresponding primary tumors for further specific targeted therapies [ 29 ].

In previous pioneering studies [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] aiming to identify EGFR mutations or distinguish between EGFR T790M-positive and negative cases, models were trained to achieve a balanced ratio between positive and negative classes, typically ranging from 0.69 to 1.17. Maintaining this equilibrium is essential during model training to prevent bias towards the majority class. However, attaining such balance can be challenging, particularly when the positive class is relatively rare. To address this challenge, various resampling techniques have been developed, including oversampling methods that generate additional data for the minority class and undersampling methods that reduce the data volume of the majority class. The hybrid approach combines elements of both oversampling and undersampling, optimizing the dataset for improved classification performance, especially for rare conditions [ 36 , 37 , 38 ].

In the current study, our primary objective is to identify the EGFR T790M mutation in brain metastases of NSCLC patients using MR radiomic features. To achieve this goal, we systematically explore different resampling techniques and machine-learning classifiers. This research aims to enhance our understanding of the most effective strategies for accurate classification within the context of an imbalanced dataset.

2 Materials and methods

2.1 patient enrollment.

A retrospective analysis was conducted on a consecutive cohort of 1679 patients diagnosed with NSCLC. These patients underwent gadolinium-enhanced brain MRI between 2010 and 2019 under the approval of the local Institutional Review Board (IRB2022059, approved on 14th July 2022) at Ditmanson Medical Foundation Chia-Yi Christian Hospital. According to the approved IRB protocol (IRB2022059), the requirement for informed consent was waived. This decision was made because the study utilized anonymized brain MRI images and corresponding molecular data, ensuring patient confidentiality through a complete de-linking process. The waiver was granted in accordance with existing policies and IRB approval. The data analysis was conducted in accordance with the approved guidelines (IRB2022059) by the Institutional Review Board at Ditmanson Medical Foundation Chia-Yi Christian Hospital.

The inclusion criteria encompassed the following: (1) Pathologically confirmed diagnosis of NSCLC; (2) Diagnosis of brain metastasis via brain MRI; and (3) MR imaging before treatment. Exclusion criteria comprised: (1) Brain metastasis originating from sources other than lung cancer; (2) Clinical lung cancer stage I, II, or III; (3) Extra-brain parenchymal metastasis, including calvarium, pachymeninges, leptomeninges, liver, adrenal, or bone; (4) No testing results of EGFR mutation status; (5) Artifacts or missing sequences in brain MR examinations. The flowchart of patient selection is shown in Fig.  1 . Adhering to these criteria, a total of 125 patients were enrolled in the final study cohort, with 18 patients classified as T790M-positive and 107 as T790M-negative. The clinical and MRI characteristics of the enrolled patients are provided in Table  1 .

The flowchart of patient selection

2.2 MRI research protocol

Brain MR images were retrieved from the picture archiving and communication systems at Ditmanson Medical Foundation Chia-Yi Christian Hospital. Specifically, 58 T790M-negative and 8 T790M-positive cases were conducted using a 1.5 T Signa™ HDxt scanner (GE Healthcare, Milwaukee, WI) equipped with an eight-channel neurovascular array GE coil and the software of HD 16.0_V03_1638.a. Additionally, 49 T790M-negative and 10 T790M-positive cases were performed using a 1.5 T Optima™ MR450w (GE Healthcare) scanner with a 16-channel GE head-and-neck unit coil and the software of DV25.1_R05_2131.a.

2.3 The brain MR examination protocols included various sequences

These sequences consisted of fast spin echo (FSE) T1-weighted image (T1WI) with the following parameters: TE = 24 ms, rephasing RF pulse = 160°, FOV = 220 mm × 220 mm, section thickness = 6 mm, gap = 0.6 mm, and matrix = 320 × 224. Additionally, FSE T2-weighted image (T2WI) was included with TE = 106 ms, rephasing RF pulse = 160°, FOV = 220 mm × 220 mm, section thickness = 6 mm, gap = 0.6 mm, and matrix = 320 mm × 192 mm. The TR values for T1WI and T2WI were automatically determined based on the slice number using the scanner vendor's operating software. Typically, TR values for T1WI were shorter than 700 ms, while those for T2WI were longer than 2000 ms. The examination also featured FSE T2 fluid-attenuated inversion recovery (T2FLAIR) with TR/TE = 9000/140 ms, inversion time (TI) of 2200 ms, rephasing RF pulse 160°, FOV = 220 mm × 220 mm, section thickness 6 mm, gap 0.6 mm, and matrix = 320 × 224. Single-shot echo-planar imaging diffusion-weighted imaging (DWI) was conducted with TR/TE = 8000/76.6 ms, FOV = 240 mm × 240 mm, section thickness = 6 mm, gap = 0.6 mm, matrix = 128 × 128, and a b value of 1000 s/mm 2 . Furthermore, gadolinium-enhanced T1-weighted imaging (CET1WI) was performed. The CET1WI sequence was acquired after the intravenous administration of gadobutrol (Gadovist®, 0.1 mmol/kg body weight). For the DWI sequences, the array spatial sensitivity encoding technique was implemented to accelerate image acquisition. It's important to note that all acquired MR images were in two-dimensional (2D) format.

2.4 Imaging processing

All the images were resized to a matrix size of 450 × 450. Two radiographers (K.-M. L. and C.-H. C.) independently selected regions of interest (ROIs) based on CET1WI images. The ROI with the largest area within each patient was chosen as the representative ROI for subsequent analysis. Other sequence images (T1WI, T2WI, T2FLAIR, and DWI) were then aligned to the corresponding CET1WI images using a six-parameter rigid body transformation and mutual information algorithm. Image resizing, ROI selection, and image alignment were conducted using the Multimodal Radiomics Platform (V5.0) [ 39 ] under the environment of MATLAB 2021a (The MathWorks, Inc., Natick, MA). The similarity of the ROIs from the two radiologists was evaluated using the Dice score and Jaccard index with Pillow (9.4.0) in the Python environment (3.10.9). The images were discretized into 256 levels [ 40 ]. Subsequently, the image information was extracted, encompassing 19 first-order statistical features, 94 s-order features (including gray level co-occurrence matrix [GLCM], gray level run length matrix [GLRLM], gray level size zone matrix [GLSZM], neighboring gray-tone difference matrix [NGTDM], and gray level dependence matrix [GLDM]) for each imaging sequence, and 10 2D shape features for each ROI. Consequently, a total of 480 features were extracted from each patient (i.e., 5 imaging sequences × 94 imaging features + 10 ROI features). The image discretization and feature extraction were using PyRadiomics (v3.1.0).

2.5 Imaging analysis

The selection of ROI features was performed using backward elimination with a p-value < 0.05. Feature selection was applied to ROIs delineated independently by the two observers, and the intersection of selected features from both observers was utilized for classification. To mitigate potential bias in results stemming from the imbalanced dataset, two categories of approaches were employed. First, we utilized class weights, which adjust the weights of the loss function to emphasize the minority class and avoid biased results toward the majority class. Second, we resampled selected features using various techniques, including 5 oversampling methods (random oversampling [ROS], synthetic minority oversampling technique [SMOTE], adaptive synthetic [ADASYN], borderline SMOTE [bSMOTE], and support vector machine SMOTE [SVM-SMOTE]), 4 undersampling methods (random undersampling [RUS], cluster centroids, Tomek’s links [TL], and near miss), and 2 hybrid sampling approaches that combine oversampling and undersampling techniques (SMOTE-ENN [edited nearest neighbor] and SMOTE-TL). All resampling techniques were applied with their default parameters. For ROS, we introduced additional perturbations to the distribution of synthetic data by setting the “shrinkage” parameter to 1 and 3, denoted as ROS1 and ROS3, respectively, in addition to the default setting. Resampled features were subsequently classified using logistic regression (LR), SVM, random forest (RF), and extreme gradient boosting (XGBoost) with threefold and fivefold cross-validations. RF and XGBoost necessitated hyperparameter fine-tuning to optimize performance, with surveyed hyperparameters listed in Table S1. To avoid evaluation bias toward the majority (non-T790M mutant) class, macro-averaged precision, recall, and F1 scores were calculated in addition to the area under the receiver operating characteristic (ROC) curve (AUC). The macro-averaged F1 score provided a comprehensive evaluation of classification performance, equally considering recall and precision while mitigating the influence of imbalanced data by treating the F1 score from each class equally. We also employed SHAP values to understand the importance of the selected features in the classification. All the aforementioned procedures were implemented using scikit-learn (1.21), imbalanced-learning (0.10.1), xgboost (1.73), and shap (0.42.1) in the Python environment.

The selected CET1WI images of brain metastases from NSCLC patients are shown in Fig.  2 . There are no visually distinguishable characteristics between T790M-positive (Fig.  2 A and B) and T790M-negative (Fig.  2 C and D) cases. The Dice scores and Jaccard indices for the two observers are 0.88 ± 0.10 and 0.80 ± 0.13, respectively. The ROIs with high similarity selected by the two observers are shown in Fig.  2 A and C, while those with low similarity are shown in Fig.  2 B and D, where discrepancies usually occur in the prepheral regions of the enhancing rumor part.

Selected CET1WI images of T790M-positive ( A and B ) and T790M-negative ( C and D ) cases. The ROIs selected by observers 1 and 2 are outlined in blue and red, respectively. High similarity examples are shown in ( A and C ) while low similarity examples are shown in ( B and D )

Using backward elimination, the number of image features was significantly reduced from 480 to 20 for each of the two observers, as shown in Table S1. Twelve features were common to both independent processes. Among these common features, 2 were from T1WI, 10 from T2WI, and 1 from T2FLAIR. Specifically, the common features included 2 first-order features (energy and total energy) from T2WI and 11 s-order features across the sequences. These included 1 GLDM and 1 GLRLM feature from T1WI, 1 GLCM, 4 GLDM and 3 GLSZM features from T2WI, and 1 GLDM feature from T2FLAIR. Notably, the feature Gray Level Non-Uniformity of GLDM appeared repeatedly across all three sequences.

A systematic investigation was carried out, exploring various pairs of four different classifiers (LR, SVM, RF, and XGBoost) combined with a range of resampling techniques to address the issue of imbalanced data, utilizing the 13 selected features. Classification performance metrics, including macro-averaged F1, recall, precision, and AUC, were remarkably consistent between the two observers (Figures S1 and S2). The average performance of these two observers is presented in Figure S3. In general, RF and XGBoost demonstrated superior performance compared to LR and SVM [ 36 , 37 ]. Without employing any resampling technique, the performance metrics hovered around 0.5, with slight improvement observed with the utilization of undersampling. In contrast, both oversampling and hybrid-sampling methods yielded significantly improved classification results. Macro-averaged F1 scores ranged from 0.81 to 0.94 with RF and from 0.79 to 0.93 with XGBoost when these resampling methods were employed.

We selected ROC curves of no-sampling with LR and SVM-SMOTE with XGBoost to represent the improvement by resampling in Fig.  3 A, where the corresponding AUCs are 0.89 and 0.47, respectively. In addition to one T1WI feature, the SHAP values in Fig.  3 B indicate that the T2WI features are essential for distinguishing between T790M-positive and T790M-negative cases.

A The ROC curves of two representative combinations of resampling technique and classifier, including no-sampling + LR and SVM-SMOTE + XGBoost. B  The SHAP values of SVM-SMOTE + XGBoost

Furthermore, an attempt was made to utilize only the 10 features from T2WI features, with the aim of minimizing scanner time in clinical practice. The performance with these reduced features exhibited consistency between the two observers (not shown), and the averaged performance is illustrated in Figure S4. Notably, the classification performance using features from only T2WI images closely resembled the performance achieved with all the features.

4 Discussion

The emergence of resistance to first-line EGFR-TKIs typically occurs within 10 to 14 months of treatment, primarily due to secondary resistance caused by the EGFR T790M mutation [ 3 ], approximately 50 to 60% among the cases [ 9 ], making it crucial to detect this resistant mutation early through a non-invasive approach for tailored precision therapy.

Radiomic identification of the EGFR T790M mutation has predominantly relied on chest images [ 14 , 15 , 16 , 17 , 18 , 19 ]. However, recent studies have ventured into recognizing EGFR [ 20 , 21 , 22 , 23 , 24 , 25 ] or EGFR T790M [ 26 , 27 ] mutations through MR images of brain metastases, yielding reasonable performance (Table  2 ). The AUC for detecting EGFR mutation in these studies ranged from 0.73 to 0.99 [ 20 , 21 , 22 , 23 , 24 , 25 ]. To the best of our knowledge, only two studies have attempted to differentiate between T790M-positive and T790M-negative cases, achieving AUCs of 0.81 and 0.89 [ 26 , 27 ].

This study included a dataset of 125 cases comparable to the sample sizes in related literature (ranging from 52 to 233, Table  2 ). To minimize observer biases, two radiographers independently selected ROIs, with the areas of selected ROIs showing high Dice score (0.88 ± 0.10) and Jaccard index (0.80 ± 0.13) between observers. A total of 480 image features were extracted based on 2D shape, first-order, and second-order statistical features. Feature selection using backward elimination from both sets of ROIs yielded highly similar results, with 13 common features (Table  2 ), suggesting the analyses were based on reliable ROIs.

Out of the 13 common features, 11 were second-order statistical features, which aligns with findings in other studies where second-order features predominated [ 21 , 22 , 28 ]. This indicates the importance of the complex relationships between adjacent voxels in differentiating T790M-positive and T790M-negative cases, which may not be visually discernible. Some studies have highlighted the potential benefits of including diffusion sequences in classification [ 22 , 26 ], but the DWI features were not selected by the backward elimination in our study.

A main challenge in this study was the exceptionally low ratio of T790M-positive to T790M-negative cases, standing at only 0.17. This ratio posed a notable contrast to similar studies (Table  2 ) and necessitated the application of resampling techniques to address the dataset's severe class imbalance [ 26 , 28 , 36 , 37 , 38 ]. Consequently, we conducted a systematic exploration of classification methods, considering the combined impact of resampling approaches and classifiers. Our study leveraged four widely recognized classifiers: LR, SVM, RF, and XGBoost. Previous research has indicated that RF and XGBoost often outperform other methods in similar tasks [ 20 , 22 , 26 , 28 , 36 , 37 ]. However, it is important to note that both of these methods require meticulous parameter optimization to achieve their best performance. To this end, we conducted a thorough parameter tuning process, as detailed in Table S2, ensuring that the classifiers were operating at their optimal settings to address the unique challenges posed by our imbalanced dataset. The imbalanced data could also be addressed by increasing the weights of the loss function for the minority class. However, we did not find a substantial benefit from this approach. Regardless of the classifier used, performance metrics (Figs.  3 and S1-S4) were approximately 0.5 without resampling, suggesting a bias toward the T790M-negative class. Interestingly, under the undersampling technique, simpler classifiers (LR and SVM) performed better than complex ones (RF and XGBoost), indicating that simpler classifiers may be more efficient with smaller sample sizes. However, the metrics obtained with undersampling were only slightly improved compared to those without resampling. In general, RF and XGBoost exhibited good performance with oversampling or hybrid-sampling methods. Among the oversampling methods, ROS with RF and XGBoost yielded unusually high macro-averaged F1 scores and AUCs, which decreased with more perturbation (ROS1 and ROS3). Similarly, the AUCs for hybrid sampling (especially SMOTE-ENN) with RF and XGBoost tended to be higher. Considering the upper bound of AUC from the literature is 0.89 [ 26 ], SVM-SMOTE with XGBoost from two observers does not surpass this boundary, which might be the best model in our survey. Although the AUCs are higher than those reported in the literature, combinations of XGBoost or RF with other oversampling techniques could be promising. However, these combinations still need to be validated with a larger dataset.

We further explored the use of features from the minimum required imaging sequences to reduce scanning time. A total of 10 T2WI features were chosen for further classification (Table S1). The performance with the reduced features (Figure S4) was slightly reduced but still comparable to that with the full set of selected features (Figs.  3 and S3). This is supported by the SHAP values (Fig.  3 B), which indicate that T2WI features play an important role in the classification.

Although numerous resampling techniques have been developed to address imbalanced data, there is no gold standard to date [ 36 , 37 ]. Conducting a systematic survey may indeed be the most effective approach to comprehensively assess the performance of these resampling techniques. However, it's crucial to note that solely pursuing high-performance metrics can potentially lead to overfitting due to the generation of synthetic data. As a precaution, in our evaluation, we considered the AUC reported in the literature as the upper boundary [ 26 ]. The resampling procedure can be implemented before or after feature selection. In this study, we only considered the latter procedure. It's worth noting that different sets of features might be chosen when resampling is performed prior to feature selection, which can make it challenging to evaluate the intricate interplay between resampling techniques and classifiers. Due to the small data size in our study, model estimations with fivefold cross-validation could also result in overfitting. Therefore, we also employed threefold cross-validation for each condition (data not shown). The results from both threefold and fivefold cross-validation were comparable.

This study is accompanied by several notable limitations. Firstly, the EGFR T790M mutation status for this cohort was obtained from primary NSCLC specimens. Consequently, it was assumed that brain metastatic lesions would possess the same mutation status as their corresponding primary tumor sites. While previous research has reported low overall discordance rates in EGFR mutation status between primary lung cancer and corresponding brain metastases [ 41 ], the potential for discordance cannot be entirely ruled out. Indeed, previous studies have demonstrated discordance in EGFR expression or mutation status between primary lung cancer and corresponding metastatic sites [ 29 , 30 , 31 , 42 , 43 ]. Although there is no definitive discordance rate for T790M mutation status in primary NSCLC and brain metastases, reported rates of EGFR discordance between lung cancer and corresponding brain metastatic sites in patients have ranged from 6.7 to 32% [ 30 , 32 , 33 , 34 , 35 , 44 ]. Secondly, this study is retrospective in nature and relies on data collected over a 10-year period from a database. This extended timeframe introduces various inherent confounding variables, including differences in patient characteristics, variations in MR scanners used, and changes in imaging parameters. Finally, it is important to acknowledge that the data utilized in this study was sourced from a single institution, and external validation was not conducted. Moreover, the limited number of positive cases further constrained our analysis of the imbalanced dataset. As a result, our findings and the performance of our approach can only be assessed by comparing them to existing literature [ 26 , 27 ].

5 Conclusion

This study aimed to detect the EGFR T790M mutation in lung cancer using MR images of brain metastases within an imbalanced dataset, where the ratio of T790M-positive to T790M-negative cases was only 0.17. When considering the highest reported AUC from the literature as an upper bound (0.89), our results demonstrated that SVM-SMOTE paired with XGBoost provided the highest AUC at 0.89. However, other oversampling methods in combination with RF or XGBoost could also yield comparable performance. This study showcases that it is possible to achieve a level of performance comparable to existing literature even with an imbalanced EGFR T790M dataset. Our findings contribute to the growing body of evidence addressing imbalanced datasets in scientific research.

Data availability

Data is available on request due to ethical restrictions.

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Acknowledgements

This study was supported by the National Science and Technology Council (NSTC, Taiwan): 112-2113-M-194-007, and Ditmanson Medical Foundation Chia-Yi Christian Hospital: R111-63.

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Department of Radiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 600, Taiwan

Wen-Feng Wu, Kuan-Ming Lai & Chia-Hung Chen

Central Taiwan University of Science and Technology Institute of Radiological Science, Taichung, 406, Taiwan

Kuan-Ming Lai & Chia-Hung Chen

Department of Chemistry and Biochemistry, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, 62102, Taiwan

Bai-Chuan Wang, Yi-Jen Chen, Chia-Wei Shen, Kai-Yan Chen & Eugene C. Lin

Center for Nano Bio-Detection, National Chung Cheng University, Chiayi, 621, Taiwan

Eugene C. Lin

Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhongxiao Rd., East Dist., Chiayi City, 60002, Taiwan

Chien-Chin Chen

Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 402, Taiwan

Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 701, Taiwan

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K.-M.L. and C.-H.C. selected regions of interest. B.-C.W., Y.-J.C., C.-W.S, and K.-Y.C. analyzed the data. W.-F.W., E.C.L., and C.-C.C. designed and directed the project. W.-F.W. and E.C.L. contributed to the interpretation of the results. W.-F.W. and E.C.L. wrote the manuscript with input from all authors.

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Wu, WF., Lai, KM., Chen, CH. et al. Predicting the T790M mutation in non-small cell lung cancer (NSCLC) using brain metastasis MR radiomics: a study with an imbalanced dataset. Discov Onc 15 , 447 (2024). https://doi.org/10.1007/s12672-024-01333-1

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DOI : https://doi.org/10.1007/s12672-024-01333-1

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IO Biotech Announces Positive Results from Phase 2 Trial of IO102-IO103 in the First-line Treatment of Advanced Head and Neck Cancer

In this article:.

-- Study Meets Overall Response Rate Primary Endpoint, Encouraging Secondary Endpoint Progression-Free Survival Data in Squamous Cell Carcinoma of the Head and Neck Cohort --

-- No New Safety Signals or Added Systemic Safety Concerns Observed --

-- Data Presented at the European Society for Medical Oncology (ESMO) Congress --

NEW YORK, Sept. 14, 2024 (GLOBE NEWSWIRE) -- IO Biotech (Nasdaq: IOBT), a clinical-stage biopharmaceutical company developing novel, off-the-shelf, immune-modulating therapeutic cancer vaccines, announced promising data from the Phase 2 basket trial of IO102-IO103, the company’s lead investigational therapeutic cancer vaccine candidate, in combination with Merck’s (known as MSD outside of the United States and Canada) anti-PD-1 therapy KEYTRUDA® (pembrolizumab) (IOB-022/KN-D38) at the 2024 ESMO Congress in Barcelona from September 13-17.

The presentation contained clinical and biomarker data from a cohort of patients with recurrent or metastatic (advanced) squamous cell carcinoma of the head and neck (SCCHN) with PD-L1 CPS ≥ 20 (PD-L1 high), contributing to the growing body of research supporting the potential clinical benefit of this combination regimen for these patients. The data from 18 efficacy evaluable patients demonstrated:

Achievement of the primary endpoint – confirmed 44.4% overall response rate (ORR) in a PD-L1 high population of patients with SCCHN irrespective of HPV status.

An encouraging 6.6-month median progression-free survival (PFS).

A 66.7% disease control rate (DCR).

A safety profile consistent with previously reported data when combined with anti-PD-1 monotherapy.

T-cell responses to both IO102 (targeting IDO) and IO103 (targeting PD-L1) were detected after treatment.

“These encouraging data further support the potential of IO102-IO103 in combination with pembrolizumab as first-line treatment for patients with recurrent or metastatic SCCHN including HPV-positive and -negative patients,” stated Jonathan Riess, MD, principal investigator of the trial and Director, Thoracic Oncology at the UC Davis Comprehensive Cancer Center. “Given the need for new treatment options that are effective, safe and accessible for head and neck cancer patients, further investigation of this combination should be conducted to build on the findings of this Phase 2 trial.”

“With the data we’ve presented from studies in head and neck cancer and in melanoma, evidence is accumulating that the combination of IO102-IO103 with the anti-PD-1 therapy pembrolizumab could be a safe and efficacious first-line treatment for patients with a range of cancers, including those with metastatic and difficult-to-treat disease,” said Qasim Ahmad, MD, Chief Medical Officer of IO Biotech. “Importantly, with mPFS of 6.6 months, more than half of the patients in this trial had over 180 days of progression-free survival. These data are supportive of further investigation of this combination regimen as part of our commitment to transform the lives of cancer patients through our novel therapeutic vaccine.”

The Phase 2 basket study (IOB-022/KN-D38; NCT05077709) is a non-comparative, open-label trial to investigate the safety and efficacy of IO102-IO103 in combination with pembrolizumab as a first-line treatment in up to 60 patients with metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥ 50% and recurrent or metastatic SCCHN with PD-L1 CPS ≥ 20. The primary endpoint of the study is overall response rate. Patients enrolled in the study who had at least 2 post-baseline tumor assessments or who discontinued after 2 cycles of study treatment as of the data cut off of August 2, 2024 were considered efficacy evaluable and were included in the ESMO poster presentation.

To date, the safety profile observed in this study (OB-022/KN-D38) is consistent with prior studies of IO102-IO103 in combination with checkpoint inhibitors, with no added significant systemic toxicity compared to anti-PD1 monotherapy and low-grade transient injection site reactions reported as the most common treatment related adverse events​. The trial has completed enrollment of patients in all cohorts. Data from the non-small cell lung cancer (NSCLC) cohort of this study will also be presented at another medical meeting in the fall.

The poster can be found on the “ Posters & Publications ” page of the IO Biotech website. Details for the presentation are below:

Poster Title: A phase 2 trial of the IO102-IO103 vaccine plus pembrolizumab: completed cohort for first line (1L) treatment of advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN) Presentation number: 1022P Presenter: Jonathan W. Riess, MD, MS (UC Davis Comprehensive Cancer Center) Date: Saturday, September 14, 2024 Time: 12:00 PM – 1:00 PM CEST

About IO102-IO103

IO102-IO103 is an investigational off-the-shelf therapeutic cancer vaccine designed to kill both tumor cells and immune-suppressive cells in the tumor microenvironment (TME) by stimulating activation and expansion of T cells against indoleamine 2,3-dioxygenase (IDO) positive and programmed death-ligand 1 (PD-L1) positive cells. The company is currently conducting a pivotal Phase 3 trial (IOB-013/KN-D18; NCT05155254) investigating IO102-IO103 in combination with pembrolizumab versus pembrolizumab alone in patients with advanced melanoma, a Phase 2 basket trial (IOB-022/KN-D38; NCT05077709) investigating IO102-IO103 in combination with pembrolizumab as first line treatment in patients with solid tumors, and a Phase 2 basket trial (IOB-032/PN-E40; NCT05280314) investigating IO102-IO103 in combination with pembrolizumab as neo-adjuvant/adjuvant treatment of patients with solid tumors.

The clinical trials are sponsored by IO Biotech and conducted in collaboration with Merck, which is supplying pembrolizumab. IO Biotech maintains global commercial rights to IO102-IO103.

KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About IOB-022/KN-D38 Phase 2 Solid Tumor Basket Trial

IOB-022/KN-D38 (NCT05077709) is a non-comparative, open-label trial to investigate the safety and efficacy of IO102-IO103 in combination with pembrolizumab in first-line advanced cancers in non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). IO Biotech is sponsoring the Phase 2 trial and Merck is supplying pembrolizumab. IO Biotech maintains global commercial rights to IO102-IO103.

About IO Biotech

IO Biotech is a clinical-stage biopharmaceutical company developing novel, immune-modulating therapeutic cancer vaccines based on its T-win® platform. The T-win platform is based on a novel approach to cancer vaccines designed to activate T cells to target the immunosuppressive cells in the tumor microenvironment. IO Biotech is advancing its lead cancer vaccine candidate, IO102-IO103, in clinical trials, and additional pipeline candidates through preclinical development. Based on positive Phase 1/2 first line metastatic melanoma data, IO102-IO103, in combination with pembrolizumab, has been granted a breakthrough therapy designation for the treatment of advanced melanoma by the US Food and Drug Administration. IO Biotech is headquartered in Copenhagen, Denmark and has US headquarters in New York, New York.

For further information, please visit www.iobiotech.com . Follow us on our social media channels on LinkedIn and X ( @IOBiotech ).

Forward-Looking Statement

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements, including regarding the timing or outcome of primary analysis of the company’s Phase 3 trial, other current or future clinical trials, their progress, enrollment or results, or the company’s financial position or cash runway, are based on IO Biotech’s current assumptions and expectations of future events and trends, which affect or may affect its business, strategy, operations or financial performance, and actual results and other events may differ materially from those expressed or implied in such statements due to numerous risks and uncertainties. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. Because forward-looking statements are inherently subject to risks and uncertainties, you should not rely on these forward-looking statements as predictions of future events. These forward-looking statements speak only as of the date hereof and should not be unduly relied upon. Except to the extent required by law, IO Biotech undertakes no obligation to update these statements, whether as a result of any new information, future developments or otherwise.

Investors Maryann Cimino, Director of Investor Relations IO Biotech, Inc. 617-710-7305 [email protected]

Media Julie Funesti Salutem 917-498-1967 [email protected]

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