Treatment of locally advanced (stage III) non-small cell lung cancer

INTRODUCTION — 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. 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: Treatment of small cell lung cancer").

Once NSCLC is diagnosed, tests are usually performed to "stage" the cancer to determine how far it has progressed or spread. Cancer staging usually requires a combination of physical examination, x-ray studies, and sometimes an operation (referred to as "mediastinoscopy") 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 (show figure 1)). (See "Patient information: Diagnosis and staging of lung cancer")

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 indicating the most advanced (show table 1). The stage of a cancer is important because it helps determine the best treatment options and is generally predictive of outcome (prognosis).

The optimal treatment of stage III ("locoregionally advanced") NSCLC continues to change as results from additional trials become available. The characteristics of stage III NSCLC and the approaches to treatment will be reviewed here.

Patient information on the treatment of stage I and II NSCLC, and the management of patients with more advanced or recurrent (relapsed) disease is presented elsewhere. (See "Patient information: Treatment of early stage (stage I and II) non-small cell lung cancer" and see "Patient information: Treatment of advanced unresectable, metastatic, and recurrent non-small cell lung cancer").

DEFINITION OF STAGE III NSCLC — In patients with stage III NSCLC, the tumor has invaded the tissues in the chest more extensively than in stage II, and/or the cancer has spread to lymph nodes in the mediastinum (show table 1). However, spread ("metastasis") to other parts of the body is not detectable. Stage III is sub-divided into stages IIIA and IIIB (show figure 2).

Stage IIIA — Patients are classified as stage IIIA based upon either spread to the lymph nodes or the size and extent of the tumor. Stage IIIA cancers are divided into two large groups based upon the following (show 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.) 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 (T3N1-2).

Stage IIIB — Stage IIIB NSCLC represents more advanced disease, and includes tumors with any of the following characteristics: Spread to lymph nodes on the side of the mediastinum opposite that of the lung tumor (N3) or supraclavicular lymphnodes. 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).

Pleural effusions — 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, but an effusion is present in up to one-third of patients with newly diagnosed NSCLC. This fluid pushes against the lung, compressing it, and preventing the lung from being fully expanded when a breath is taken in, thereby causing shortness of breath.

A determination of whether or not pleural fluid contains cancer cells is important as a part of the initial evaluation in patients who have an effusion at diagnosis. A small amount of fluid is withdrawn through a needle inserted through the skin and into the pleural space (termed a "thoracentesis"). This fluid is then examined under a microscope.

For patients with newly diagnosed NSCLC, the majority of pleural effusions are due to tumor in the pleural space, indicating stage IIIB disease (show table 1). In such patients, surgery to remove the tumor is not usually appropriate. Treatment of patients with malignant pleural effusions is discussed elsewhere. (See "Patient information: Treatment of advanced unresectable, metastatic, and recurrent non-small cell lung cancer", section on Treatment of malignant pleural effusions).

In a minority of cases, no cancer cells can be 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 therapeutic options, no single approach can be recommended for all patients. Surgery, radiation therapy, and chemotherapy are options, either separately or in combination.

Surgery — Surgery is generally not used as the initial treatment in patients who are identified as stage III during the initial evaluation. In comparison, surgery represents the best choice for the initial therapy of patients with more limited (stages I and II) NSCLC (show table 1). If their overall medical condition permits, patients with stage I or II tumors generally will have their tumor surgically removed. However, after surgery, some patients are reclassified as having stage III disease because tumor is found in the mediastinal lymph nodes when the tissues removed at surgery are examined through the microscope. (See "Initial treatments" below).

Radiation therapy — Radiation therapy (RT) uses focused, high energy x-rays to destroy cancer cells. The x-rays are delivered by a large machine called a linear accelerator. Individual treatments are brief and not painful. The damaging effect of radiation is cumulative, and a certain dose must be reached before the cancer cells are killed. 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. Thus, in contrast to chemotherapy, which is a systemic or body-wide treatment (see below), RT is considered a local treatment, and 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"). Both of these conditions are usually self-limiting and improve after treatment is completed. Most patients also have some degree of fatigue and skin irritation, which looks like a sun burn 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. Most chemotherapy drugs are administered into the vein, although some agents can be given by mouth. The most common side effects of chemotherapy are fatigue and lowering of the white blood cell count which increases susceptibility to infection.

INITIAL TREATMENTS — The initial step is staging prior to treatment, to determine how far the tumor has spread. This generally includes a physical examination, blood tests, and other radiographic studies which optimally should include a PET/CT scan and often a CT or MRI of the brain. Patients with stage III disease can be divided into two groups, depending upon whether this information becomes available before or after surgical removal of the cancer. Resected stage III disease — Patients with disease that appears to be limited to the lung (stage I or II) after staging workup usually undergo resection of their tumor. When the tumor and lymph nodes are examined under the microscope after surgery, previously unsuspected tumor may be found in the mediastinal lymph nodes (N2). The tumor is thus 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 the operation, 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.

RESECTED STAGE III DISEASE — Some patients will be classified as having stage III disease (show table 1) based upon the results of surgical removal of their tumor and surrounding lung. In this situation, the surgery is both the final step in staging and the initial treatment. Even though there is no known cancer left behind, there is a very high likelihood that cancer cells are still present and that their growth will eventually produce clinical evidence of recurrence either in the chest or elsewhere in the body. Chemotherapy is often recommended after surgery in such patients to reduce the likelihood of tumor recurrence. In some instances, RT may also be recommended after surgery to prevent recurrence in the chest.

Adjuvant chemotherapy — The use of chemotherapy following a cancer operation is referred to as adjuvant chemotherapy. The rationale is that cancer cells have already spread elsewhere in the body at the time cancer is diagnosed, even though evidence cannot be found on x-rays or other tests. Thus, systemic treatment (ie, adjuvant chemotherapy) is used to try to eliminate these residual cancer cells.

Many studies have explored the use of adjuvant chemotherapy after an operation for NSCLC. The results of early trials were mixed, with some studies showing a benefit, some no benefit, and others indicating worse results for patients who receive chemotherapy. However, many of these studies did not use modern chemotherapy combinations containing a platinum compound (cisplatin or carboplatin).

When the results of these studies were combined and analyzed together, the use of cisplatin-based chemotherapy was associated with a 5 percent higher chance of survival (ie, 1 in 20 patients) five years after the diagnosis [1]. Since that analysis, several large trials have been reported examining the usefulness of adjuvant cisplatin-containing chemotherapy after surgery removed the entire lung tumor.

The potential value of this approach was illustrated by the ANITA trial, in which 840 patients with completely resected stages IB, II and IIIA NSCLC were randomly assigned to observation or chemotherapy with cisplatin plus vinorelbine (Navelbine®) [2]. In a preliminary report, overall survival was significantly improved with adjuvant chemotherapy at five years (51 versus 43 percent, compared to observation alone), and the benefits were most pronounced in patients with stage IIIA disease (42 versus 26 percent). A significant survival benefit for adjuvant chemotherapy was also seen in the JBR 10 trial sponsored by the National Cancer Institute of Canada [3].

Although two other trials did not show a significant benefit from adjuvant cisplatin-containing chemotherapy [4,5], the overall results suggest that adjuvant cisplatin-based chemotherapy offers the best chance of improving long-term survival in patients with stage III NSCLC that has apparently been removed by surgery.

Postoperative RT — For patients thought to have had their cancer removed, the use of RT after surgery (termed postoperative or adjuvant radiation therapy) decreases the chance that the tumor 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 [6].

Despite the prevention of local recurrence, postoperative RT has not been shown to improve the overall survival rate 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 or not surgery removed all of the cancer or there is evidence of residual cancer left behind after surgery.

UNRESECTED STAGE III DISEASE — Surgery is generally not recommended as the initial treatment if mediastinal lymph nodes are affected and the tumor has not yet been removed. In selected situations, there may be a role for surgery later in the course, after other therapies have been given.

Historically, most of these patients were treated with RT alone. However, results from large clinical trials have showed that a combination of RT and chemotherapy is the preferred approach in patients with unresected stage III NSCLC.

Combined radiation therapy and chemotherapy — Combination therapy, involving the use of both chemotherapy and RT, appears to work better than either RT or chemotherapy alone for patients with unresectable stage III NSCLC.

The first approach used was to give chemotherapy prior to RT (termed "sequential therapy"), to minimize toxicity. Subsequently, better results were reported when full doses of chemotherapy and RT are administered at the same time (termed "concurrent chemoradiotherapy") rather than sequentially [7-9]. Concurrent chemoradiotherapy has replaced the sequential use of these two approaches, and is generally preferred for patients with unresected stage III disease.

The efficacy of this approach is illustrated by a Japanese study in which 320 patients with unresectable stage III NSCLC were randomly assigned to chemotherapy plus RT given at the same time or to the same chemotherapy regimen followed by RT [7]. Concurrent chemoradiotherapy was associated with increased survival at five years compared to sequential therapy, although the rate of survival was still low (16 versus 9 percent).

Role of surgery — Although a tumor may decrease in size following RT and chemotherapy, it usually does not disappear entirely. Eventually, the cancer may grow back in the same location (termed a local recurrence). In some cases, RT and chemotherapy may produce enough tumor shrinkage that surgery can then be used to remove any remaining tumor. Although using surgery may prevent local recurrence, it remains uncertain whether this improves the long-term outcome; as a result, the use of surgery remains an area of active investigation.

The value of this approach was examined in a trial in which 429 patients with unresected stage IIIA NSCLC were treated initially with concurrent RT and chemotherapy [10]. Patients whose tumors decreased in size in response to treatment were randomly assigned to either additional RT to the chest or to surgery to remove residual tumor. The median survival of both groups, RT plus chemotherapy or RT plus chemotherapy and resection was 22 months. The use of surgery was associated with a trend toward better long-term survival (27 versus 20 percent at five years), but this difference was not significantly different. These findings were due to an increased number of deaths during or immediately after the operation, particularly among those having an entire lung removed ("pneumonectomy").

Additional results from other trials will be helpful in determining whether or not surgery is actually beneficial after chemoradiotherapy.

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 patients 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.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

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

(www.cancernet.nci.nih.gov/)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The American Cancer Society

(www.cancer.org)
Lung Cancer Alliance

(www.lungcanceralliance.org)



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