Stage 4 Non-Small Cell Lung Cancer: Staging, Treatment, Prognosis

Stage 4 non-small cell lung cancer (NSCLC), also called metastatic lung cancer, is the most advanced stage of this disease. It refers to any size and type of NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) that has spread from one lung to the other lung, to another region of the body, or to the fluid around the lung or heart. Stage 4 NSCLC is not curable but it is treatable.

Nearly 40% of people who learn they have lung cancer are already at stage 4 of the disease when they're newly diagnosed. Thankfully, in recent years, several advances in treatments have significantly improved survival.

Staging

The first step to diagnosing stage 4 cancer is an X-ray or computed tomography (CT) scan, but a lung biopsy is usually necessary to make a clear determination.

To determine what stage your cancer is, healthcare providers use a standard system from the American Joint Committee on Cancer (AJCC). It is called the TNM system, with each letter in the acronym standing for a different observable characteristic of the cancer.

• Tumor (T): Healthcare providers measure the size of the primary tumor and how close it is to other body organs.
• Nodes (N): Tests are used to determine whether the cancer has spread to nearby lymph nodes.
• Metastasis (M): Using scans, biopsies, genetic testing, or other means, healthcare providers check whether lung cancer cells have spread to distant organs such as the brain, bones, adrenal glands, liver, or the other lung.

Numbers or letters are used after the T, N, and M notations to indicate how advanced the tumor, lymph node progression, and metastases are.

Stage 4 cancer is broken into two groups: 4A and 4B (with 4B being the most advanced).

Of note, small-cell lung cancer (which is different and rarer than NSCLC) involves only two stages: limited and extensive.

Stage 4 NSCLC Symptoms

Stage 4 NSCLC symptoms may vary based on the location of tumors and how far the cancer has spread.

Problems due to the presence of a tumor in the lungs include:

• Persistent cough
• Coughing up blood (hemoptysis)
• Shortness of breath
• Hoarseness
• Pain the chest, back, shoulder or arms
• Repeated episodes of pneumonia or bronchitis
• Wheezing

As cancer metastasizes, symptoms are related to the area where the cancer has spread. For example:

• Abdominal pain and jaundice (a yellowing of the skin) from a tumor that has spread to the liver
• Headaches, memory loss, vision problems, and weakness if a tumor spreads to the brain
• Pain in the back, hips, shoulders, and chest when cancer has spread to bone
• Difficulty swallowing due to a tumor being near the esophagus

These symptoms may be accompanied by fatigue, unintentional weight loss, and loss of appetite.

Treatments

Because stage 4 NSCLC has spread beyond the lungs, it is considered inoperable. It cannot be cured, but it is treatable. New medications have helped people live longer, fuller lives while managing this disease.

Targeted Therapies

Using in-depth genetic testing (molecular profiling) of your tumors, healthcare providers are able to identify genetic mutations in cancer cells. Based on this data, they can plan a personalized approach to your care and incorporate targeted therapies—medications that act on these genes to halt the disease's progression.

Your healthcare provider will probably recommend that you undergo genetic testing before you begin any other treatment. If these biomarker tests reveal that tumors show DNA changes, there may be medications that you can take that will target those mutations.

For instance, if there is an EGFR mutation, it means that cancer cells are carrying out cell division at an excessive rate. You may then be given tyrosine kinase inhibitors (TKIs), targeted therapy drugs that send signals to the cells to stop that growth.

These TKIs don't work for all EFGR mutations, though. In May 2021, the Food and Drug Administration (FDA) approved the use of Rybrevant (amivantamab-vmjw) for people who have the third-most common kind of EGFR mutations, called EGFR exon 20 insertion mutations. This different kind of targeted therapy may help people with this mutation when cancer has progressed during or after platinum-based chemotherapy treatments.

Medications are approved by the FDA for several other genetic abnormalities, including ALK, ROS-1, NTRK, MET, RET, and BRAF V600E. Examples include the drugs Krazati (adagrasib) and Lumakras (sotorasib). They target the KRAS G12C mutation, found in about 13% of people with NSCLC. Both were recently approved for use in patients with advanced or metastatic disease after other therapies have been tried.

Initially, BRAF mutations were found in people with metastatic melanoma but are now discovered in approximately 4% of people with NSCLC. 

Researchers have found that people with different cancer types harboring BRAF mutations often respond to treatment with BRAF inhibitors (usually in combination with a MEK inhibitor). For example, the BRAF inhibitor Tafinlar (dabrafenib) and the MEK inhibitor Mekinist (trametinib).

Chemotherapy

Historically, chemotherapy was the main option available to advanced lung cancer patients. These medications kill cancer cells, but they also have difficult-to-manage side effects that not all people are able to tolerate. With new chemotherapy drugs, side effects are less severe and there is the benefit of long survival with treatment.

If genetic testing shows no treatable genomic alterations, chemotherapy will likely be recommended, often along with immunotherapy. Chemo may also be used alone as palliative care for those with very advanced cancer who want to ease their symptoms.

Immunotherapy

Immunotherapy is another newer type of treatment for lung cancer that stimulates your own immune system to recognize and fight cancer cells. People who have tumors that are PD-L1 positive and/or have a high number of mutations (called a high tumor mutational burden) may respond best to these medications. Those who have genomic alterations, such as EGFR mutations, tend not to respond as well.

While they don't work for everyone, some people with advanced non-small cell lung cancer have experienced long-term control of their disease with these drugs.

Radiation Therapy

Radiation therapy, such as stereotactic body radiotherapy (SBRT), delivers high doses of radiation directly to a tumor to kill it. This won't stop aggressive stage 4 non-small cell lung cancer that has spread, but it may be recommended as palliative therapy.

This can be helpful for some people to control symptoms of brain metastases, bone pain, bleeding from the lungs, or difficulty breathing caused by tumors that are obstructing the airways.

Clinical Trials

Treatments for lung cancer are continually being researched and improved upon. The National Cancer Institute (NCI) runs clinical trials that test new treatments for advanced non-small cell lung cancer.

You can use their online database to search for trials seeking participants.

Prognosis

The overall 5-year survival rate for stage 4 non-small cell lung cancer is approximately only 4% but can be much higher in certain populations. The median survival time (time at which 50% of patients are alive and 50% have died) is about eight months.

Coping

Healthcare providers often say that learning what you can about your lung cancer can improve your quality of life and possibly even your outcome. Ask questions. Learn about clinical trials. Consider joining a support group.

Many people hesitate to talk about end-of-life issues, but discussing these with your healthcare provider and your family is associated with fewer feelings of loneliness and a better quality of life. Never lose hope. Even if you have chosen not to pursue further treatment, you can hope for quality time with loved ones and good control of your symptoms.