Patient information: Non-small cell lung cancer treatment; locally advanced (stage III) cancer

NON-SMALL CELL LUNG CANCER OVERVIEW

Non-small cell lung cancer (NSCLC) represents about 85 percent of all lung cancers; the remaining 15 percent are small cell lung cancers. These two types of lung cancer behave differently and are treated in a different manner. The management of small cell lung cancer is discussed elsewhere. (See "Patient information: Small cell lung cancer treatment".)

The characteristics of locally advanced (stage III) NSCLC and the approaches to treatment will be reviewed here.

The treatment of stage I and II NSCLC and the management of patients with more advanced or recurrent (relapsed) disease are presented elsewhere. (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; advanced unresectable, metastatic (stage IV), and recurrent cancer".)

NON-SMALL CELL LUNG CANCER STAGING

Once NSCLC is diagnosed, tests are performed to determine how far the cancer has progressed or spread; this is called staging. Cancer staging usually requires a combination of a physical examination, x-ray studies, and sometimes an operation (referred to as mediastinoscopy or mediastinotomy) to evaluate the lymph nodes in the center of the chest (this area is called the mediastinum, and the lymph nodes contained within the mediastinum are called mediastinal lymph nodes (figure 1)). (See "Patient information: Lung cancer risks, symptoms, and diagnosis".)

Depending upon the extent of the lung cancer, a tumor stage (I, II, III, or IV) is assigned, with stage I disease representing the earliest cancers, and stage IV indicating the most advanced (table 1). The stage of the lung cancer is important because it helps determine the best treatment options and is generally predictive of outcome (prognosis).

DEFINITION OF STAGE III NON-SMALL CELL LUNG CANCER

In patients with stage III NSCLC, the tumor has invaded the tissues in the chest and/or the cancer has spread to lymph nodes in the mediastinum (table 1). However, spread (metastasis) to other parts of the body is not detectable. Stage III is divided into stages IIIA and IIIB (figure 2).

Stage IIIA — Stage IIIA cancers are divided into two large groups based upon the following (table 1):

• Involvement of lymph nodes in the mediastinum on the same side as the tumor, or just below the carina, regardless of the size of the primary tumor (T1-3, N2). The carina is the point at which the trachea, the tube that carries air to the lungs, splits in two to reach the right and left lung (figure 1).
• Growth of the cancer into the chest wall or other nearby chest structures, collapse of the lung, or growth by the tumor to within 2 cm of the carina, in conjunction with spread to lymph nodes within the lung or mediastinum on the same side as the tumor (T3, N1-2).

Stage IIIB — Stage IIIB NSCLC represents more advanced disease, and includes tumors with any of the following characteristics:

• Spread to lymph nodes (N3) on the side of the mediastinum opposite the lung tumor or to lymph nodes located above the collarbone (called supraclavicular lymph nodes).
• Growth into other structures in the chest, such as the trachea, esophagus, bones of the spine, the heart, or blood vessels leading to the heart (T4).
• Presence of cancer-containing fluid in the pleural space (termed a malignant pleural effusion).

The term pleural effusion refers to a collection of fluid within the chest that is located not inside the lung, but in the pleural space, which is a pocket between the actual lung and the tissues of the chest wall. This space is normally empty.

It is important to determine if pleural fluid contains cancer cells. To do this, a procedure is called a thoracentesis is done. This involves withdrawing fluid through a needle that is inserted through the skin and into the pleural space. This fluid is then examined under a microscope. (See "Patient information: Thoracentesis".)

For patients with newly diagnosed NSCLC, the majority of pleural effusions are due to tumor in the pleural space, indicating stage IIIB disease (table 1). People with malignant pleural effusions are treated similarly to people with stage IV NSCLC, which is discussed elsewhere. (See "Patient information: Non-small cell lung cancer treatment; advanced unresectable, metastatic (stage IV), and recurrent cancer", section on 'Treatment of malignant pleural effusions in non-small cell lung cancer'.)

In a minority of cases, no cancer cells are found and the pleural effusion is simply a reaction to the presence of the tumor. In such patients, the stage of the tumor is not affected by the presence of the pleural effusion.

TREATMENT OPTIONS

While there are many treatment options for stage III NSCLC, no single approach is best. The best option depends upon the stage of the cancer and your health and preferences. Options include surgery, radiation therapy, and chemotherapy.

Surgery — Surgery is generally not recommended as the first treatment for people with stage III non-small cell lung cancer (table 1).

Radiation therapy — Radiation therapy (RT) uses focused, high energy x-rays to destroy cancer cells. Treatments are brief and not painful. To minimize damage to normal cells, small doses of RT are administered daily, five days per week, for several weeks.

RT is only directed to the areas of the body that are affected by the tumor. As a result, side effects are largely limited to the area that is being treated. These side effects occur because normal tissues near the tumor inevitably are also exposed to the radiation.

The most common side effects are difficulty swallowing due to inflammation of the esophagus (esophagitis) and inflammation of the normal lung surrounding the tumor (pneumonitis). Esophagitis is usually temporary and improves after treatment is completed. Pneumonitis usually occurs within several months after the completion of RT and can cause cough and shortness of breath. These symptoms can usually be controlled with medications. Most people also have some degree of fatigue and skin irritation, which looks like a sunburn on the chest.

Chemotherapy — 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, except bone marrow (where the blood cells are produced), hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment. The most common side effects of chemotherapy are fatigue and lowering of the white blood cell count, which increases susceptibility to infection.

Most chemotherapy drugs are administered into the vein, although some agents can be given by mouth.

INITIAL TREATMENTS

People with stage III disease can be divided into two groups, depending upon whether they are diagnosed with stage III cancer before or after surgery.

• Resected stage III disease — People with lung cancer that appears to be limited to the lung (stage I or II) after staging workup usually undergo surgical removal (resection) of their tumor. When the tumor and lymph nodes are examined under the microscope after surgery, previously undetected tumor cells can be found in the mediastinal lymph nodes (N2). The tumor is then reclassified as stage IIIA, rather than stage I or II.
• Unresected stage III disease — If cancer is shown to involve the mediastinal lymph nodes based on the staging studies done before surgery, surgical removal of the tumor and surrounding lung is not usually recommended as the initial treatment. Instead, a combination of chemotherapy and radiation therapy (RT) is recommended.

TREATMENT AFTER SURGERY

Some people will be classified as having stage III disease (table 1) based upon tissue that is obtained during surgery. Even though there is no visible cancer left behind after surgery, there is a very high likelihood that cancer cells are still present and that their growth will eventually produce a recurrence of cancer, either in the chest or elsewhere in the body.

In this group of patients, chemotherapy is often recommended after surgery to reduce the likelihood of tumor recurrence. In some instances, radiation therapy may also be recommended after surgery to prevent recurrence in the chest.

Adjuvant chemotherapy — The use of chemotherapy following surgery is referred to as adjuvant chemotherapy. A systemic treatment (ie, adjuvant chemotherapy) is used to try to eliminate any residual lung cancer cells that may be left after surgery.

Many studies have explored the use of adjuvant chemotherapy after an operation for NSCLC. Studies that included the drug cisplatin showed that patients who were given chemotherapy had a 5 to 10 percent higher chance of survival five years after surgery [1]. The benefits of chemotherapy were most pronounced in people with stage II or III disease.

Postoperative RT — The use of RT after surgery (termed postoperative or adjuvant radiation therapy) decreases the chance that the lung cancer will recur at its original site (termed a local recurrence). In one study, for example, the rate of local recurrence was only 3 percent in patients who received postoperative RT, compared to 41 percent in those who did not receive RT [2].

However, postoperative RT does not appear to improve the overall survival following surgery. This is because RT is a local treatment and does not prevent the development of distant tumor spread (metastases). However, postoperative RT is often recommended if there is any uncertainty about whether surgery removed all of the lung cancer or if there is evidence of residual cancer left behind after surgery.

TREATMENT IF SURGERY IS NOT AN OPTION

Surgery is generally not recommended as the initial treatment for lung cancers that involve the mediastinal lymph nodes (N2 or N3 disease) before surgery. Surgery is also not usually recommended first for people whose tumors invade vital structures, such as the heart, esophagus, or major blood vessels (T4). In selected situations, there may be a role for surgery later in the course, after other therapies. This section will discuss the treatments recommended for people who have not yet had surgery

Radiation therapy and chemotherapy — Combination therapy, involving the use of both chemotherapy and RT, appears to work better than either radiation therapy or chemotherapy alone for people with stage III non-small cell lung cancer who have not had surgery. About 20 percent of people treated with chemotherapy are alive five years after diagnosis.

Concurrent chemoradiotherapy — The preferred approach is to give full dose cisplatin-based chemotherapy and RT at the same time (termed concurrent chemoradiotherapy) rather than giving chemotherapy before radiation therapy (termed sequential therapy). Concurrent chemoradiotherapy is associated with increased survival at five years compared to sequential therapy, although studies show that the rate of survival is still low (16 versus 9 percent).

This regimen is usually given as follows:

• Radiation therapy is performed once per day, five days per week for approximately 6 weeks. The dose is broken up into small daily doses to minimize side effects and damage to normal tissues.
• The most commonly used chemotherapy drugs include cisplatin and etoposide. These drugs are usually given into a vein over 3 to 5 days during the first and fifth week of radiation therapy; each treatment takes between 1 and 6 hours.

Sequential therapy — If you cannot tolerate the side effects of chemoradiotherapy or if the tumor is initially too large to treat with radiation therapy, chemotherapy alone may be given to shrink the tumor. Once the size of the tumor is reduced, radiation therapy may be recommended.

Radiation therapy alone — If a person is very ill or has an active infection due to blockage of a main airway in the lung, then the safest and most effective treatment may be with radiation therapy alone, without chemotherapy. In this situation, most people will have shrinkage of the cancer and improvement in symptoms, although the tumor will almost always recur at some time in the future.

Role of surgery — Although a tumor may decrease in size following radiation therapy and chemotherapy, it usually does not disappear entirely. Eventually, the lung cancer grows back in the same location (termed a local recurrence). In some cases, radiation therapy and chemotherapy shrink the tumor enough that surgery can be done to remove any remaining tumor. Although surgery may prevent a local recurrence, it is not clear if surgery improves your long-term outcome; as a result, the use of surgery remains an area of active investigation.

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: Small cell lung cancer treatment
Patient information: Non-small cell lung cancer treatment; early stage (stage I and II) cancer
Patient information: Non-small cell lung cancer treatment; advanced unresectable, metastatic (stage IV), and recurrent cancer
Patient information: Lung cancer risks, symptoms, and diagnosis
Patient information: Thoracentesis

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

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.

• The National Library of Medicine

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

• National Cancer Institute

      (www.cancernet.nci.nih.gov/)

• American Society of Clinical Oncology

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

• Global Resource for Advancing Cancer Education (GRACE)

      (www.cancerGRACE.org/lung)

• Lung Cancer Alliance

      (www.lungcanceralliance.org)

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