Overview of Stage Four Lung Cancer

What is Stage Four Lung Cancer?

In stage four lung cancer, cancer has spread to other regions of the body, which is called metastasis. Stage four is the most advanced cancer stage. Lung cancer is commonly already in stage four when it is first diagnosed. The National Cancer Institute estimates that about 55% of lung or bronchus cancers are first diagnosed at this stage. Understanding the stage and type of cancer is critical in determining the most appropriate treatment option for any patient. It is also important to consider the individualized goal of treatment. Late-stage disease that has metastasized and is widespread throughout the body is often considered incurable. In this case, the goal of treatment is to control/ shrink the tumor, reduce symptoms, continue a positive quality of life, and try to prevent further metastasis and subsequent complications.

Lung cancer can be divided into the following two subcategories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is the more common type, making up roughly  85% of lung cancer cases. Stage four NSCLC can be further divided into 4A or 4B. The ‘B’ grouping makes up the majority of late-stage cases and involves multiple sites of metastasis, which are distant from the lungs.

All lung cancer is also described using the TNM staging system. Using this method, the cancer is characterized by assigning numerical values to the three following components: tumor (T), lymph nodes (N), and metastasis (M). It is the combination of an individual T, N, and M classification that is used to derive an overall Stage of I-IV. As an example, a patient with a T1, N1, M0, or NSCLC would be considered stage  IIA. All lung cancer patients will have a T, N, and M grouping as well as a prognostic stage group I-IV.

Diagnosing Stage Four Lung Cancer

Doctors may utilize a variety of scans to diagnose, stage, and evaluate metastasis in lung cancer. The most common scans include:

• Magnetic Resonance Image (MRI) with contrast is a type of scan commonly used to evaluate if the disease has spread to other parts of the body. It uses magnetic waves to create images. Typically, an MRI is used to determine if cancer has spread to the brain.
• Computed tomography (CT) scan with contrast works similarly to an MRI, except it uses x-rays to generate a picture of the body. CT scans are commonly used to determine if cancer has spread to sites outside of the central nervous system (CNS).
• Positron emission tomography (PET) scans are also used to evaluate the cancer and the extent of metastasis to other organs by examining the cell’s metabolic activity.
• Most patients with lung cancer will have a CT scan of the chest, abdomen, and pelvis, an MRI of the brain, and a PET scan.

Lung Cancer Life Expectancy

Lung cancer remains the leading cause of cancer-related deaths in the United States. . The stage at diagnosis has a significant impact on the prognosis of the disease and treatment options.

The 5-year survival rate for patients that are first diagnosed with stage IV lung cancer is about 5-10%. In late-stage disease, the cancer has spread to other organs, contributing to an overall poor prognosis. The 5-year survival rate is considerably higher if the lung cancer is caught during its earlier stages. However, the 5-year survival rate is projected to continue to improve with advances in modern medicine. Most notably, genetic testing, immunotherapy, improvements in radiation delivery, increased screening uptake,  and targeted medication use is helping patients live longer.

The Graded Prognostic Assessment is a tool that can be used to evaluate patients’ prognoses. It considers the following factors during prognosis evaluation: cancer type, patient’s age, patient’s functional impairment, the presence of metastases outside the brain, number of brain metastases, and presence of genetic biomarkers and certain proteins.

Who is at the Highest Risk?

There are several factors that are known to influence lung cancer survival. The type of cancer, location of the tumors, and extent of metastasis play a significant role in the prognosis, with more widespread disease contributing to a shorter life expectancy. The patient’s age, gender, physical health, and other comorbid conditions upon diagnosis also affect survival. The immune systems of older patients are less able to fight the cancer on their own, which contributes to a worse survival rate compared to younger patients. Men have a poorer prognosis and are statistically more likely to get lung cancer. It is also known that smoking is a major risk for getting lung cancer initially, but not stopping smoking upon diagnosis instead, it negatively impacts survival. Even if patients do not stop smoking until after being diagnosed with lung cancer, smoking cessation can still improve survival.

Complications of Stage Four Lung Cancer

Metastasis

In stages two and three, the cancer spreads to the lymph nodes, but in stage four, the cancer spreads or metastasizes to other organs. Metastasis is the process by which cancerous cells break off from the original tumor and travel either through blood vessels or the lymphatic system to another distinct part of the body. The most common sites of metastasis in stage four lung cancer are the brain, liver, bone, and adrenal glands. One study found that liver and bone metastases were associated with the worst survival, while nervous system or brain metastases were the most common.

Symptoms

The symptoms of lung cancer can be quite varied. Common symptoms include the following:

• Persistent coughing or coughing up blood
• Difficulty breathing
• Weight loss
• Chest pain
• Fatigue
• Recurrent lung infections
• Change in Voice

In late-stage lung cancer, the disease has already spread to different organs. Complications can be due to the metastases, such as:

• Seizures
• Jaundice
• Headaches
• Confusion
• Bone pain

Lung Cancer Biomarker and Genetic  Testing

Genetic testing of lung cancer helps to guide treatment decisions. Specifically, there are targeted therapy options available if a patient has certain genetic biomarkers, sometimes called ‘driver mutations.’ Cancer cells that have genetic mutations continue to multiply, and each copy contains the same genetic mutation. Targeted therapies work using these specific mutations. Performing genetic testing prior to treatment is critical. Common mutations that have approved drugs include:

• EGFR gene mutation
• KRAS gene mutation
• ALK rearrangement
• ROS1 rearrangement

There are also immunotherapy medications available based on the expression of certain proteins in the cancer cells. Special tests are used to evaluate the expression of these proteins. In tumors that have an overexpression of said proteins, it can be expected that certain immunotherapy drugs would be especially useful.

Cancerous cells can be tested for these genetic mutations using two techniques. The first is a biopsy in which a physical sample of the tumor is removed and tested. The second method is through a liquid biopsy or blood test. Liquid biopsies are currently only used when tissue can’t be obtained from traditional biopsies.  It is critical that these genetic mutations and biomarkers are evaluated because the use of targeted therapies is possible; these medications have proven to be more effective than traditional chemotherapy and often have fewer or more tolerable side effects. They also have better side effects profiles because the tumor is specifically targeted, and healthy tissue is not damaged.

Treatment for Stage Four Lung Cancer

The type of lung cancer, NSCLC or SCLC, and the extent and location of both the primary tumor and any metastases play an important role in therapy selection. The presence of genetic mutations and the expression of certain immune system proteins help the treatment plan to become further individualized.

Immunotherapy

Immunotherapy drugs work by using the body’s natural immune system to fight the cancer cells. When immunotherapy drugs were new, they were typically only used in stage four lung cancer. They are now being used earlier in disease progression. These medications are used in the treatment of both SCLC and NSCLC. For example, checkpoint inhibitors are immunotherapy drugs that work by preventing the cancer cells from making or binding protective proteins. PD-1 is a protein in immune cells, and PD-L1 is a protein that is made by some healthy cells. When the PD-1 and PD-L1 proteins bind together, that tells the immune system not to attack that particular cell. Cancer cells produce these proteins, which protect them from the immune system. Checkpoint inhibitors disrupt this process. CTLA-4 is another immune protein that works similarly. PD-1, PD-L1, and CTLA-4 are all targets for immunotherapy drugs.

Targeted Therapy

Most patients who test their cancer for genetic mutations will not have a mutation that matches currently approved targeted therapies. However, for the patients that do, it can change the prognosis significantly. Targeted therapies are very specific and work with certain genetic mutations in the cancer to control it. Because they are so specific, they also tend to have much fewer side effects than non-specific treatments, such as chemotherapy. Although targeted therapies do not necessarily cure the cancer, the treatment can control the growth and spread of the cancer for several years in some cases. Eventually, patients will become resistant to these targeted therapies, and they will have to change their course of treatment.

Radiation Therapy

In the treatment of stage four lung cancer, one of the main uses of radiation is to reduce the symptom burden by shrinking the tumor. If the metastasis is minimal, it may also be used to treat the tumor. The most common type of radiation is external beam radiation therapy (EBRT), which uses x-rays.

Chemotherapy

Chemotherapy alone used to be the mainstay of treatment for stage four lung cancer. It is now often used in combination with other treatment options, such as immunotherapy, radiation therapy, or targeted medications. Chemotherapy is important in stage four cancer because often, more localized treatment options, like focused radiation or surgery, are no longer possible due to the extent of the disease and metastasis. Systemic treatment of the body with chemotherapy is useful to slow the progression of further growth of the primary cancer, prevent future metastasis, and relieve symptoms associated with existing tumors. However, chemotherapy works by killing all cell types, healthy or cancerous, that are multiplying quickly, so it does have significant side effects for the healthy tissue.

Surgery

If surgery is possible, it is typically part of the initial treatment. Often, surgery is no longer an option in stage four because of the extent of the disease and the number/location of metastases. If it is not an option at diagnosis, it may become an option later in treatment after chemotherapy, immunotherapy, or targeted medications control the disease.

Palliative Care

Palliative care is a more holistic approach to treatment that focuses on symptom management and improved overall quality of life for the patient. It is often thought to be synonymous with end-of-life care. However, palliative care can and ideally should be started at diagnosis. The team of medical providers works together to reduce the burden of the disease, both in terms of symptoms and mental/emotional stress. Towards the end of disease progression, it may become more of the focus than traditional treatment options. Early use of palliative care has been shown to improve symptoms and, in some cases, increase survival times.

Moving Forward – Living with Late-Stage Lung Cancer

Due to advancements in the diagnosis and treatment of stage four lung cancer, patients are living longer with this disease. Targeted medications and immunotherapies are allowing patients to live with their cancer controlled for years. Traditional treatment options, such as surgery, radiation, and chemotherapy, are also improving for the better. There are many resources and online support available to patients to help navigate this complicated diagnosis.