INTRODUCTION

Stage IV non-small cell lung cancer includes cancers that have spread to areas beyond the chest, like the brain (figure 1). Stage IV cancer also includes people who have a fluid collection around the lung (called a malignant pleural effusion) caused by the cancer.

Stage IV non-small cell lung cancer cannot be cured, but treatment can reduce pain, ease breathing, and extend and improve quality of life.

Treatment of stage I to III non-small cell lung cancer is discussed separately. (See "Patient information: Non-small cell lung cancer treatment; stage I to III cancer (Beyond the Basics)".) More detailed information about stage IV non-small cell lung cancer is available by subscription. (See "Overview of the treatment of advanced non-small cell lung cancer".)

PERSONALIZED TREATMENT

An improved understanding of the biology of non-small cell lung cancer has led to the recognition that there are a number of different forms of non-small cell lung cancer and that certain treatments are more effective in one type and other treatments are more effective in others. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

In many cases, very specific molecular abnormalities have been found, and these identify the different types of non-small cell lung cancer. These can be identified by an analysis of the DNA from the tumor by looking for specific changes (mutations). New treatments developed to specifically address these abnormalities are referred to as targeted therapy. When such changes are not found, a more general approach, chemotherapy, is usually preferred. Surgery might be an option in some patients if the cancer has spread to a single place outside the lung.

TARGETED THERAPY

Targeted therapy is the name for anticancer treatments that interfere with how a cancer grows and spreads when a very specific abnormality is present. These treatments work in a different way than standard chemotherapy. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

The decision about which targeted therapy, if any, to use depends on your particular cancer. Generally, a sample of your tumor that was obtained by surgery or biopsy is analyzed in the laboratory to make this decision. When such an abnormality is present, the likelihood of a favorable response to treatment is much higher than with older forms of treatment such as chemotherapy.

Testing can be done to see if your cancer belongs to one of the categories that is likely to respond to targeted therapy.

• Epidermal growth factor receptor (EGFR) mutations – When the epidermal growth factor receptor contains a particular abnormality (mutation), this change can stimulate growth and spread of the tumor. Erlotinib (Tarceva) and gefitinib (Iressa) are targeted chemotherapy medicines that block the growth of the tumor in this situation. If an abnormality in EGFR is found, targeted therapy is generally used instead of standard chemotherapy. The most common side effects of erlotinib and gefitinib are skin rash and diarrhea. Gefitinib is not available in the United States. (See "Initial systemic therapy for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor".)
• Anaplastic lymphoma kinase (ALK) gene abnormalities – A fusion (combination) of the ALK gene with another gene such as EML can drive the growth of some non-small cell lung cancers. Crizotinib (Xalkori) is a targeted medicine that blocks the cancer stimulus caused by this ALK abnormality. Crizotinib is more effective than standard chemotherapy in patients with lung cancer containing this abnormality, and thus crizotinib is generally recommended as the initial therapy instead of standard chemotherapy in this situation. Crizotinib is generally well tolerated, and the most common side effects of crizotinib are mild changes in vision and nausea, vomiting, and diarrhea. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Crizotinib'.)
• Other specific abnormalities, such as mutations in the genes ROS-1, RET, or KRAS, are being studied and may lead to specific treatments. In some cases, you may want to consider participating in a clinical trial of new agents, if your tumor contains one of these abnormalities.

If your initial treatment with a targeted agent does not work, or if you initially respond and then your disease progresses, your doctor may recommend treatment with chemotherapy.

CHEMOTHERAPY

When no specific abnormality is identified, chemotherapy is generally recommended to treat stage IV non-small cell lung cancer. Chemotherapy can often slow or stop the growth of tumors at least temporarily.

Chemotherapy is given to slow or stop the growth of cancer cells. It is not given every day but instead is given in cycles. A cycle of chemotherapy (typically about 21 days) refers to the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines. Your healthcare provider can describe which chemotherapy drugs will be needed. (See "Initial systemic chemotherapy for advanced non-small cell lung cancer without an epidermal growth factor receptor mutation or the ALK fusion oncogene".)

Most treatments involve a combination (regimen) of two chemotherapy drugs. The most commonly used regimens include either cisplatin (Platinol) or carboplatin (Paraplatin); this is combined with one of several other drugs (such as pemetrexed [Alimta], paclitaxel [Taxol], docetaxel [Taxotere], gemcitabine [Gemzar], vinorelbine [Navelbine]).

Most of the drugs are given into a vein (intravenous, IV) once every three weeks. In some cases, your doctor will recommend combining these chemotherapy drugs with bevacizumab (Avastin), a medicine that blocks a protein called vascular endothelial growth factor (VEGF).

Four to six cycles of chemotherapy are usually recommended, depending upon your response to treatment. In many cases, your doctor may recommend continuation of treatment with one drug after the four cycles of chemotherapy, if you have had a favorable response to the initial treatment.

If your initial chemotherapy treatment does not work, or if you initially respond and then have progressive disease, your doctor may recommend treatment with other chemotherapy medications or a targeted agent such as erlotinib.

Side effects — The most serious side effect of chemotherapy is a temporary drop in your blood count. This can increase your risk of developing an infection. Blood counts typically fall 7 to 14 days after the chemotherapy is given. During this time, you should call your doctor or nurse immediately if you develop chills or have a fever (temperature higher than 100.4ºF or 38ºC).

A number of other side effects are possible and these include:

• Temporary hair loss
• Numbness in the fingers and toes (called neuropathy)
• Nausea and vomiting
• Skin rash

Treatment for older people and those who are ill — Some people are not healthy enough to have a chemotherapy regimen with two drugs as described above. This might include people who are older or who have another serious illness. In this case, treatment with one chemotherapy medicine (rather than two) or with a targeted therapy (see 'Targeted therapy' above) may be an option. This type of treatment can prolong survival and improve quality of life. The side effects of one chemotherapy medicine are not as severe as when two are used.

MANAGEMENT OF METASTASES IN NON-SMALL CELL LUNG CANCER

The brain, the bones, and the area around the lungs (the pleural space) are common places for cancer to spread in people with non-small cell lung cancer. Cancer that has spread to the brain or bones is called metastatic lung cancer, not brain cancer or bone cancer.

In some cases, certain areas of spread require particular treatment directed toward the metastases.

Malignant pleural effusion — A pleural effusion is a collection of fluid in the chest that is located in the pleural space, a pocket between the lung and the tissues of the chest wall (figure 1). This space is normally empty, although it can accumulate fluid in people with advanced lung cancer. The fluid pushes against the lung, compressing it and preventing the lung from fully expanding when breathing. Thus, the most common symptom of a pleural effusion is shortness of breath.

In most people with advanced lung cancer, the pleural effusion is caused by the cancer. This is called a malignant pleural effusion. (See "Management of malignant pleural effusions".)

Treatment of the pleural effusion is usually recommended for people who develop shortness of breath. Shortness of breath often worsens as more fluid accumulates.

The simplest way to treat a pleural effusion is to insert a small tube (a catheter) into the space around the lung and allow the fluid to drain out. Afterward, the catheter is removed. This is called a thoracentesis. Thoracentesis can usually be done in the office or hospital room using local anesthesia.

If the fluid reaccumulates quickly, meaning that you need another thoracentesis in less than one month, a more aggressive treatment might be recommended. This includes a catheter that is left in place (a tunneled catheter) or using a substance to block the build-up of fluid (called pleurodesis).

• Tunneled catheter – Some people are treated with a catheter that is left in the pleural space and connected to a container. This is called a tunneled catheter. The patient (or a family member) uses a vacuum bottle to drain the fluid once a day or as needed. The catheter is usually inserted during a day surgery procedure. It is left in place for several weeks or months, as long as the fluid continues to drain. The advantage of a catheter over other treatments is that it allows the patient and their doctors to manage the fluid collection out of the hospital.
• Pleurodesis – Another option for treating a malignant effusion is called chemical pleurodesis. This involves draining the fluid and then applying a substance (usually talcum powder) to the surface of the lung, which helps prevent the fluid from collecting again. This treatment is usually done in the hospital and requires a three- to five-day stay. It may be associated with temporary pain and fever for a few days.

Brain metastases — Symptoms of brain metastases can include:

• Headache (often in the morning)
• Weakness
• Trouble thinking clearly
• Seizures (convulsions)

If your doctor is concerned about brain metastasis, he or she will order a magnetic resonance imaging (MRI) study or CT scan. Treatments for brain metastases include radiation therapy and medicines to reduce brain swelling (steroids).

People who have one or a small number of metastases in the brain are sometimes offered more aggressive treatment. This might include surgery to remove tumor(s) in the brain. Stereotactic radiosurgery (also called the gamma knife) is an alternative to surgery in selected patients. Stereotactic radiosurgery uses high doses of radiation in a small area given in small number of treatments. Both surgery and stereotactic radiosurgery are often combined with radiation therapy to the entire brain to prevent the regrowth of the cancer in the brain. (See "Overview of the clinical manifestations, diagnosis, and management of patients with brain metastases".)

Bone metastases — Bone metastases, the spread of lung cancer to one or more bones, can cause pain or fractures. There are several options for treating bone metastases: targeted therapy, chemotherapy, radiation therapy, and a medicine called a bisphosphonate.

• Targeted therapy or chemotherapy can often shrink or slow the growth of bone metastases, since these medicines act throughout the body (see 'Targeted therapy' above and 'Chemotherapy' above).
• Radiation therapy can reduce bone pain caused by metastases. This treatment is a good option for people with severe bone pain caused by metastasis in one or a limited number of areas. The treatment usually begins to relieve pain within one week after treatment. The treatment is given in one or a few doses, similar to having an X-ray. (See "Radiation therapy for the management of painful bone metastases".)
• Medicine (either a bisphosphonate or denosumab) might be used to prevent bone-metastasis-related problems, like fractures and bone loss. If your caregiver recommends this treatment, you should have any important dental work done first. There is a risk of a serious problem in the jaw bone related to dental work done after treatment when these drugs are used to treat bone metastases. (See "Bisphosphonates and denosumab in patients with metastatic cancer".)

PALLIATIVE CARE

Stage IV lung cancer cannot be cured. However, early integration of palliative care into the treatment of patients with advanced non-small cell lung cancer may improve quality of life. This can include assessment of physical and psychological needs and the goals for care.

Deciding when to stop treating the cancer can be difficult and should involve the patient, family, friends, and the healthcare team. Ending cancer treatment does not mean ending care. Hospice care is frequently recommended when a person is unlikely to live longer than six months. Hospice care involves treatment of all aspects of a patient's and family's needs, including the physical (eg, pain relief), psychological, social, and spiritual aspects of suffering. This care can be given at home or in a nursing home or hospice facility and usually involves multiple care providers, including a doctor, registered nurse, nursing aide, a chaplain or religious leader, a social worker, and volunteers.

These providers work together to meet the patient's and family's needs and significantly reduce their suffering. For more information about hospice, see www.hospicenet.org. (See "Hospice: Philosophy of care and appropriate utilization in the United States".).

CLINICAL TRIALS

Progress in treating lung cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

• www.cancer.gov/clinicaltrials/
• http://clinicaltrials.gov/

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Lung cancer (The Basics)
Patient information: Non-small cell lung cancer (The Basics)
Patient information: Lung cancer screening (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Non-small cell lung cancer treatment; stage I to III cancer (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Overview of the initial evaluation, treatment and prognosis of lung cancer
Diagnosis and staging of non-small cell lung cancer
Pathology of lung malignancies
Overview of the treatment of advanced non-small cell lung cancer
Personalized, genotype-directed therapy for advanced non-small cell lung cancer
Initial systemic therapy for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor
Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer
Initial systemic chemotherapy for advanced non-small cell lung cancer without an epidermal growth factor receptor mutation or the ALK fusion oncogene
Advanced non-small cell lung cancer: Maintenance therapy after initial chemotherapy
Systemic therapy for advanced non-small cell lung cancer in elderly patients and patients with a poor performance status
Overview of the clinical manifestations, diagnosis, and management of patients with brain metastases
Radiation therapy for the management of painful bone metastases
Bisphosphonates and denosumab in patients with metastatic cancer
Management of malignant pleural effusions
Hospice: Philosophy of care and appropriate utilization in the United States

The following organizations also provide reliable health information.

• National Cancer Institute

     1-800-4-CANCER
     (www.nci.nih.gov)

• American Society of Clinical Oncology

     (www.cancer.net/portal/site/patient)

• National Comprehensive Cancer Network

     (www.nccn.com)

• Global Resource for Advancing Cancer Education (GRACE)

     (www.cancerGRACE.org/lung)

• Lung Cancer Alliance

     (www.lungcanceralliance.org)