Patient information: Non-small cell lung cancer treatment; advanced unresectable, metastatic (stage IV), and recurrent cancer

NON-SMALL CELL LUNG CANCER OVERVIEW

Non-small cell lung cancer (NSCLC) represents between 75 and 85 percent of all lung cancers; the remaining 15 to 25 percent are small cell lung cancers, which tend to behave differently and are treated differently.

This topic discusses the management of patients with advanced, metastatic (stage IV), and recurrent NSCLC. Treatment for stage IV disease is not intended to cure the cancer; instead, treatment focuses on the following:

• Slowing the effects of the disease
• Prolonging survival
• Diminishing symptoms
• Maximizing the person's comfort

Other stages of NSCLC are discussed separately. (See "Patient information: Non-small cell lung cancer treatment; early stage (stage I and II) cancer" and "Patient information: Non-small cell lung cancer treatment; locally advanced (stage III) cancer".)

NON-SMALL CELL LUNG CANCER STAGING

Once a NSCLC is diagnosed, tests are performed to "stage" the cancer, or determine how far it has progressed or spread. Staging of the cancer usually requires a combination of physical examination, x-ray studies, and sometimes, an operation to evaluate the lymph nodes in the center of the chest (this area is called the mediastinum) (figure 1).

Depending upon the extent of the cancer, a tumor stage (I, II, III, or IV) is assigned, with stage I disease representing the earliest cancers, and stage IV, the most advanced (table 1 and table 2) ). The stage is an important piece of information as it plays a key role in determining treatment options, particularly surgery. The staging of lung cancer is discussed in detail elsewhere. (See "Patient information: Lung cancer risks, symptoms, and diagnosis".)

Stage IV lung cancer — Patients with advanced unresectable NSCLC include those whose tumor cannot be removed with surgery, usually because the cancer has spread, or metastasized, to locations beyond the chest (table 1 and table 2). These patients are said to have stage IV disease (figure 2). Treatments for people with stage IV lung cancer are not capable of curing the cancer, but can reduce symptoms and extend and improve the quality of the person's life.

This group also includes patients with pleural effusions, where the cancer has spread to the space around the lungs.

GENERAL TREATMENT INFORMATION

Surgery is not usually recommended for people with advanced NSCLC because surgery is not able to remove all of the metastases outside the lung and throughout the body. Chemotherapy is the primary form of treatment because it is better able to stop or slow growth of these metastases. However, some patients with advanced disease, such as those with a single small lesion in the lung or a single metastatic lesion to the brain, may benefit from surgery.

CHEMOTHERAPY FOR NON-SMALL CELL LUNG CANCER

Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment.

In general, side effects are more frequent when two or more drugs are administered simultaneously (termed combination chemotherapy, see below) and with higher as compared to lower doses of chemotherapy. Many chemotherapy drugs that are used for the treatment of NSCLC are administered into the vein because they are not effective when given by mouth. Newer drugs are often given orally.

Most chemotherapy drugs are administered over a one to three day period, every three to four weeks, and then restarted again. The waiting period is necessary to allow the effects of the drugs on normal tissues to subside before administering more chemotherapy (see 'Side effects' below. The short period when the drug is given, followed by the waiting period, is called one "cycle" of chemotherapy.

Benefit of chemotherapy — Patients who are given chemotherapy for advanced unresectable NSCLC generally live longer than those who are given only supportive care (by several weeks to months). Supportive care does not aim to treat the cancer, but can make the person more comfortable. (See 'End of life care' below.)

People who are given chemotherapy are approximately twice as likely to be alive one year later compared to those who are given supportive care only [1]. In addition to this survival benefit, chemotherapy also improves quality of life, even though chemotherapy often causes treatment-related side effects. This is because patients given chemotherapy tend to have better pain control and fewer symptoms related to their lung cancer.

Choice of regimen — Several types of chemotherapy (called chemotherapy "regimens") are effective for the treatment of advanced NSCLC. Patients are generally given a combination of two agents, even though such combinations often cause more side effects. The reason two agents are used is that patients given combination therapy are more likely to have a decrease in the size of their cancers (ie, a higher "response rate") and may live longer [1,2] compared to those given a single agent [3].

Adding bevacizumab — The addition of a third drug, the targeted chemotherapy drug bevacizumab (Avastin®), to a two drug chemotherapy combination appears to be a significant advance compared to earlier regimens. Bevacizumab targets a protein called vascular endothelial growth factor (VEGF), which is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread.

Bevacizumab blocks the VEGF and interferes with tumor growth. It also enhances the antitumor effect of other chemotherapy drugs. It is usually given into a vein (IV) once every three weeks. Currently, bevacizumab is recommended for use only in nonsquamous NSCLC (eg, adenocarcinoma) that is unresectable (cannot be removed with surgery), locally advanced, recurrent, or metastatic [4,5].

Bevacizumab is not suitable for all patients because it can cause severe hemorrhage (heavy bleeding) in a small percentage of patients. Thus, patients with brain metastases and those who cough up blood or take warfarin (Coumadin) are not candidates for treatment with bevacizumab because of the increased risk of serious or even fatal episodes of bleeding.

Cetuximab — Cetuximab is a targeted chemotherapy drug that works by binding to the epidermal growth factor receptor (EGFR) on the surface of the cancer cells. Cetuximab may be used in addition to chemotherapy.

Is there a best regimen? — The results of trials that included bevacizumab or cetuximab suggest that adding one of these targeted chemotherapy drugs to a two drug combination may offer the best chance to control the disease:

• Bevacizumab may be particularly useful in patients with nonsquamous lung cancers, as long as the patient does not cough up blood or have brain metastases.
• Cetuximab may be useful for patients whose cancer expresses EGFR.

For patients who are considering bevacizumab or cetuximab, it is important to understand both the potential benefits (a small increase in length of survival) and risks (bothersome or even fatal side effects).

Chemotherapy in patients who are elderly — People who are elderly need to be managed on an individual basis. Guidelines from the American Society of Clinical Oncology recommended single agent therapy in this group [6]. However, patients who are elderly but in good physical condition (also known as functional capacity) and who have no other serious medical conditions can often be treated with a platinum-based combination, such as carboplatin and paclitaxel or gemcitabine. Bevacizumab should be used with caution in people who are elderly because of the increased risk of serious side effects.

Functional capacity is often measured with a performance status scale (table 3) according to how well the patient is getting along. Patients who have a performance status of 2 or less are considered to have a limited functional status. These patients are probably best treated with a single chemotherapy medication. People who are elderly and who are at risk for significant chemotherapy-induced side effects are best treated with single-agent or non-platinum chemotherapy.

Side effects — Chemotherapy affects normal cells as well as the cancer cells, resulting in a range of possible side effects. While receiving chemotherapy, patients must be closely monitored for these side effects and any signs of drug toxicity.

The most important side effect is a temporary drop in the blood counts due to the effect of chemotherapy on the bone marrow. This typically occurs 7 to 14 days after the chemotherapy is given. During this time, the patient should immediately report any fever or chills to the physician because having low blood counts can lower resistance to infection. The highest risk of a life threatening or fatal infection occurs when the person has a low white blood cell count and fever. Other possible side effects include hair loss, numbness in the fingers and toes (called neuropathy), hearing loss, diarrhea, skin rash, and changes in kidney function.

In light of the similar effectiveness among the various chemotherapy regimens, the choice is often made based upon their side effect profile.

Treatment duration — The number of chemotherapy cycles is usually determined by how the cancer is responding to treatment and how the patient's body is tolerating the treatment. However, the optimal duration of therapy for patients who are responding well to treatment is unclear. Such patients may either continue therapy until they reach the "best response" by x-ray studies or until the cancer begins to grow despite continued therapy.

The benefit of continued therapy must be balanced against the increased likelihood of side effects with longer treatment. The optimal duration of chemotherapy that maximizes benefit and minimizes treatment-related side effects is unknown. In one study specifically designed to answer this question, patients with advanced NSCLC were given one of two treatments [7]:

• Four cycles (12 weeks of therapy) with paclitaxel plus carboplatin, which was then discontinued. Treatment was resumed (with single agent paclitaxel) only at the time of progression of disease by x-ray studies.
• Continuous treatment with both paclitaxel and carboplatin until the cancer began to grow again by x-ray studies.

When four cycles of treatment were compared to continuous combination therapy, response rates (22 versus 24 percent) and the likelihood of surviving one year (28 versus 34 percent) were similar. However, the likelihood of treatment-related neurologic side effects was twice as high in people given continuous therapy.

The American Society of Clinical Oncology guidelines for treatment of unresectable NSCLC recommend that first-line chemotherapy be limited to four to six cycles in duration and discontinued in patients who have not responded after four cycles [6]. If bevacizumab is used in combination with chemotherapy, it is usually continued after completion of the four to six cycles of chemotherapy, until the person develops signs of progression of their cancer.

Maintenance treatment — Pemetrexed (Alimta®) is a chemotherapy drug that may be recommended for patients who are doing well after their initial chemotherapy treatment. Recent results suggest that using pemetrexed after the initial chemotherapy may prolong survival in some patients.

Targeted therapy — Recent advances in understanding the biology of lung cancer have led to the ability to identify patients who are likely to respond very well to medications such as gefitinib or erlotinib. Lung cancer tumors are often tested for these molecular changes, and if present, these drugs may be used instead of chemotherapy as a first treatment.

RECURRENT NON-SMALL CELL LUNG CANCER

The majority of tumors will eventually grow again despite an initial favorable response to chemotherapy. In such cases, an alternative chemotherapy regimen may benefit patients who still have good performance or functional status. Options for treatment include single agent chemotherapy or targeted chemotherapy.

Single agent chemotherapy — Treatment with either docetaxel or pemetrexed has been shown to prolong survival and improve quality of life when used as second-line treatment. Pemetrexed is generally preferred because it is associated with fewer side effects [8].

Targeted chemotherapy — Erlotinib (Tarceva®) and gefitinib (Iressa®) are targeted chemotherapy agents that block a specific molecule (epidermal growth factor receptor or EGFR).

Targeted chemotherapy seems to work best in people whose tumors contain a particular molecular abnormality. This abnormality is most commonly found in those of Asian descent, women, lifelong nonsmokers, and in people who have a specific types of NSCLC called adenocarcinoma or bronchioloalveolar cancer. However, the drugs are active in all groups of patients.

The most common side effects of these drugs are skin rash and diarrhea.

Radiation therapy — Short courses of radiation therapy (RT) are useful for patients who have symptoms that interfere with quality of life, such as shortness of breath caused by blockage of the airway, difficulty swallowing, or spitting up blood. RT is also useful in the management of metastatic disease outside the chest, such as for painful bone metastases or brain metastases. (See 'Management of brain metastases in non-small cell lung cancer' below.)

MANAGEMENT OF BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER

The brain is a common site of distant metastasis in patients with NSCLC. Symptoms of brain metastases can include headache (often in the morning), weakness, changes in mental status, and seizures (convulsions). The diagnosis of a brain metastasis is confirmed with a magnetic resonance imaging (MRI) study or CT scan. Occasionally, a biopsy may be necessary to confirm the diagnosis. Radiation therapy and medications to reduce brain swelling (steroids) are often used to help manage symptoms. Unfortunately, the prognosis for patients who have multiple brain metastases is poor.

In contrast, patients who have one or a limited number of metastatic lesions in the brain and no other sites of metastasis may benefit significantly from more aggressive treatment. For these patients, surgical removal of the brain metastasis followed by radiation therapy of the entire brain can prolong survival. Surgical removal of the primary lung tumor (usually after treatment of the brain disease) may be considered in carefully selected cases if there are no other sites of spread of the cancer.

Stereotactic radiosurgery (gamma knife treatment) is an alternative to conventional surgery in selected patients and may provide results that are comparable to conventional surgery for some patients. Stereotactic radiosurgery does not actually require surgery, but instead uses high dose radiation in a small area. This treatment is usually used in conjunction with radiation therapy to the entire brain to decrease the risk of recurrence.

For patients who have extensive disease outside the brain, surgery and stereotactic radiosurgery for the brain metastasis are generally not appropriate. Surgery and/or radiosurgery may be recommended to reduce headaches, weakness, changes in mental status, and/or seizures. Radiation therapy of the brain may lengthen survival modestly.

TREATMENT OF MALIGNANT PLEURAL EFFUSIONS IN NON-SMALL CELL LUNG CANCER

The term pleural effusion refers to a collection of fluid within the chest that is located in the pleural space, a pocket between the lung and the tissues of the chest wall. 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 primary symptom of a pleural effusion is shortness of breath.

In people with lung cancer, the majority of pleural effusions contain cancer cells. People with malignant pleural effusions have advanced disease. Although this is classified as stage IIIB under the current staging system (table 2), the proposed new staging system classifies these as stage IV (table 1).

Shortness of breath often worsens as more fluid accumulates. Thus, treatment of the pleural effusion is sometimes necessary. A summary of the treatment options for malignant pleural effusions is presented in the following table (table 4).

Drainage plus talc — The standard treatment of a malignant effusion is to drain the fluid. A substance is then applied to the pleural space to try to eliminate the space in which the fluid accumulates. The most commonly used substance for this purpose is talcum powder or talc. There are two ways to perform this treatment.

Chest tube drainage with talc slurry — The fluid is drained from the pleura over several days using a chest tube. Talc is instilled into the pleura with the tube in a slurry (a thick mixture of talc and sterile water). This procedure is called tube thoracostomy. The procedure is done in the hospital at the patient's bedside under local anesthesia.

Thoracoscopy with talc poudrage — Thoracoscopy is performed in the operating room under general (or infrequently, local) anesthesia. The fluid is completely drained using a lighted scope, which guides the placement of a tube into the pleural space. Following fluid drainage, the surgeon sprays powdered talc over the surface of the pleura.

Thoracoscopic application of the talc does not appear to provide superior results compared to use of a talc slurry. However, in one large study specifically designed to compare the two methods, the patients treated with thorcoscopy had greater comfort and felt safer, despite a higher number of respiratory complications from the surgery [9].

Indwelling catheter — Some patients are treated with an indwelling tunneled catheter (PleuRx™) that is placed into the pleural space and connected to a container. The patient (or a family member) uses a manual pump to drain the fluid from the pleural space once a day or as needed. Tunneled catheters do not require the use of talc and generally have a lower risk of respiratory complications [10]. The catheter can be placed during a day surgery procedure. It allows the patient and their clinicians to manage the pleural effusion out of the hospital. In many centers, the tunneled catheter is replacing talc pleurodesis as the procedure of choice for treating malignant pleural effusions, especially in the following situations:

• An area of the lung is blocked by tumor, which prevents the lung from expanding completely
• The patient wants to avoid hospitalization and is willing to manage the catheter
• The patient is debilitated or life expectancy is limited

END OF LIFE CARE

In some people with lung cancer, the disease cannot be cured. 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 for the patient. 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 and family's needs, including the physical (eg, pain relief), psychological, social, and spiritual aspects of suffering. This care may be given at home or in a nursing home or hospice facility, and usually involves multiple care providers, including a physician, registered nurse, nursing aide, a chaplain or religious leader, a social worker, and volunteers.

These providers work together to meet the patient 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".)

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/clinical_trials/learning/

       www.cancer.gov/clinical_trials/

       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. Because no two people are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Non-small cell lung cancer treatment; early stage (stage I and II) cancer
Patient information: Non-small cell lung cancer treatment; locally advanced (stage III) cancer
Patient information: Lung cancer risks, symptoms, and diagnosis

Professional Level Information:
Adjuvant systemic therapy in resectable non-small cell lung cancer
Bronchioloalveolar carcinoma
Cigarette smoking and other risk factors for lung cancer
Diagnosis and staging of non-small cell lung cancer
Initial systemic chemotherapy for advanced non-small cell lung cancer
Investigational approaches for advanced non-small cell lung cancer
Management of malignant pleural effusions
Management of stage I and stage II non-small cell lung cancer
Management of stage III non-small cell lung cancer
Molecular markers in non-small cell lung cancer
Multiple primary lung cancers
Overview of the initial evaluation, treatment and prognosis of lung cancer
Pancoast's syndrome and superior (pulmonary) sulcus tumors
Pathology of lung malignancies
Role of imaging in the staging of non-small cell lung cancer
Sequential non-cross-resistant therapy for patients responding to initial treatment of advanced non-small cell lung cancer
Small molecule epidermal growth factor receptor inhibitors for advanced non-small cell lung cancer
Hospice: Philosophy of care and appropriate utilization

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

• 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)

• The National Library of Medicine

      (www.nlm.nih.gov/medlineplus/lungcancer.html)

• Lung Cancer Alliance

      (www.lungcanceralliance.org)

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