Zanmbeel

Friday, October 12, 2007

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)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311:899.
2. Douillard, J, Rosell, R, Delena, M, et al. ANITA: Phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (OBS) in completely resected (stage I-III) non-small-cell lung cancer (NSCLC) patients (pts): Final results after 70-month median follow-up.On behalf of the Adjuvant Navelbine International Trialist Association. Proc Am Soc Clin Oncol 2004; 23:615a. Abstract available online (http://www.asco.org/ac/1,1003,_12-002643-00_18-0034-00_19-0030407,00.asp, accessed on 6/8/2005).
3. Winton, T, Livingston, R, Johnson, D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352:2589.
4. Scagliotti, GV, Fossati, R, Torri, V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 2003; 95:1453.
5. Waller, D, Fairlamb, DJ, Gower, N, et al. The Big Lung Trial: determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC). Preliminary results in the surgical setting (abstract). Proc Am Soc Clin Oncol 2003; 22:632a.
6. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. The Lung Cancer Study Group. N Engl J Med 1986; 315:1377.
7. Furuse, K, Fukuoka, M, Kawahara, M, Nishikawa, H. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999; 17:2692.
8. Curran, WJ, Scott, C, Langer, C, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III non small cell lung cancer: RTOG 9410. Proc Am Soc Clin Oncol 2003; 22:621a. Abstract available online (http://www.asco.org/ac/1,1003,_12-002643-00_18-0023-00_19-00102234,00.asp, accessed 5/26/05).
9. Albain, KS, Crowley, JJ, Turrisi AT, 3rd, et al. Concurrent Cisplatin, Etoposide, and Chest Radiotherapy in Pathologic Stage IIIB Non-Small-Cell Lung Cancer: A Southwest Oncology Group Phase II Study, SWOG 9019. J Clin Oncol 2002; 20:3454.
10. Albain, KS, Swann, Rs, Rusch, VR, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol 2005; 23:624s. Abstract available online (http://www.asco.org/ac/1,1003,_12-002643-00_18-0034-00_19-0030938,00.asp, accessed 5/26/05).

Treatment of early stage (stage I and II) non-small cell lung cancer

INTRODUCTION — Non-small cell lung cancer (NSCLC) accounts for between 75 and 85 percent of all lung cancers; the remaining 15 to 25 percent are small cell lung cancers. This distinction is important when considering treatment.

Once a NSCLC is diagnosed, tests are performed to determine how far it has progressed or spread. This is referred to as "staging" the cancer. Cancer staging 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, and the lymph nodes contained within the mediastinum are called mediastinal lymph nodes) (show figure 1).

Depending upon the findings of these procedures, a specific tumor stage (I, II, III, or IV) is assigned, with stage I disease representing the earliest cancer, and stage IV, the most advanced (show table 1) [1]. The stage is an important piece of information in patients with NSCLC because it determines treatment options. The staging of lung cancer is described in detail elsewhere. (See "Patient information: Diagnosis and staging of lung cancer").

The characteristics of early stage NSCLC (stage I and stage II disease), and the treatment options that are available for these patients will be reviewed here. The treatment of small cell lung cancer is discussed elsewhere. (See "Patient information: Treatment of small cell lung cancer").

DEFINITION OF STAGE I AND II DISEASE — Patients with stage I or II NSCLC are considered to have "local" disease, with a low likelihood that the tumor has spread beyond one side of the chest.

Stage I — At this stage, tumor is present in the lungs but the cancer has not been found in the chest lymph nodes or in other locations outside of the chest. Stage I NSCLC is subdivided into stages IA and IB, mainly based upon the size of the tumor (show figure 2).

Stage IA — The tumor is 3 centimeters (cm) or less in size and has invaded nearby tissue minimally, if at all. The cancer has not spread to the lymph nodes or to any distant sites.

Stage IB — The tumor is more than 3 cm in size, has invaded surrounding tissue, or has caused a portion of the lung to collapse. The cancer has not spread to the lymph nodes or to any distant sites.

Stage II — At this stage, the cancer has either begun to involve the lymph nodes within the chest or has invaded chest structures and tissue more extensively. However, no spread can be found beyond the involved side of the chest, and the cancer is still considered a local disease. Stage II is subdivided into stages IIA and IIB (show figure 3).

Stage IIA — The tumor is 3 cm or smaller and has invaded nearby tissue minimally, if at all. One or more lymph nodes on the same side of the chest are involved, but there is no spread to distant sites.

Stage IIB — Stage IIB is assigned in two situations: when there is a tumor larger than 3 cm with some invasion of nearby tissue and involvement of one or more lymph nodes on the same side of the chest; or for cancers that have no lymph node involvement, but have either invaded chest structures outside the lung or are located within 2 cm of the carina (the point at which the trachea, or the tube that carries air to the lungs, splits to reach the right and left lungs.)

TREATMENT — Whenever possible, surgery should be considered for patients with stage I or II NSCLC since it is associated with the highest chance for cure. Radiation therapy and chemotherapy may be recommended in some patients.

An exception to these recommendations is with stage II NSCLC Pancoast tumors. These are located in the top part or apex of one of the lungs, in a region called the superior sulcus. They are unique in their presenting signs and symptoms and in the way they are treated. (See "Pancoast tumors" below).

Surgery — Surgery to remove the cancer is the preferred treatment for stage I and stage II NSCLC. Lobectomy (removal of one part (lobe) of the lung) through an open thoracotomy (large incision in the patient's chest) is the procedure of choice for patients with stages I and II NSCLC, and is preferred over pneumonectomy (removal of the entire affected lung) if the lesion can be completely removed. A pneumonectomy may be necessary if lobectomy cannot completely remove the tumor. Pneumonectomy requires that the remaining lung be healthy and strong enough to meet the patient's oxygen needs.

A more limited procedure is appropriate for those who are unable to tolerate conventional lobectomy. Limited resections are not recommended for tumors >3 cm in size whenever possible.

Outcomes — Outcomes of surgery vary according to the stage of the cancer, and to a lesser extent, the number of lung cancer surgeries performed in a patient's particular hospital. Patients who are treated in high volume centers tend to have slightly better outcomes compared to those undergoing treatment in low volume hospitals that see fewer patients with NSCLC. Stage I disease — Surgery alone is quite effective in treating stage I NSCLC. Studies have found that between 60 and 70 percent of patients with stage I NSCLC treated with surgery are still alive five years after the operation, and are presumably cured of their cancer. Stage II disease — Although surgery is less effective in treating patients with stage II NSCLC, it can cure many of these patients as well. Five year survival rates for patients with stage II NSCLC generally range between 30 and 40 percent.

Many patients with lung cancer have other lung conditions that increase their risk for complications following surgery. In particular, patients who are smokers may have chronic obstructive pulmonary disease (COPD, also called emphysema) that affects the lungs' ability to function. Breathing tests are usually performed before surgery to evaluate lung function and to predict how removal of a lung (or portion of a lung) will affect a patient's ability to breathe postoperatively. Occasionally, the tests may indicate that the risks of surgery are too great and that other forms of treatment must be used.

Radiation therapy — Radiation therapy involves the use of focused, high energy x-rays to destroy cancer cells. The x-rays are delivered from a machine (called a linear accelerator) that is outside of the patient. Treatments are brief and not painful. The damaging effect of radiation is cumulative, and a certain dose is required to stop the growth of cancer cells. In order to accomplish this, small radiation doses are administered daily, five days per week, for several weeks.

Radiation is administered to the areas of the body that are affected by the cancer. Thus, in contrast to chemotherapy, which is a systemic or body-wide treatment (see below), radiation is a local treatment, and side effects are generally limited to the area undergoing radiation. These side effects occur because some normal tissues next to the tumor inevitably are exposed to some of the radiation. The most common side effects are difficulty swallowing due to inflammation of the gastrointestinal tract (termed esophagitis) and inflammation of the normal lung surrounding the tumor (termed pneumonitis). Both of these conditions are usually self-limited and improve after treatment is completed.

Radiation alone may be used to treat patients with stage I or stage II NSCLC who are unable to tolerate or who are not interested in surgery. Although not as effective as surgery, it is more effective than no treatment at all. Studies suggest that among patients with stage I or stage II disease who receive radiation therapy alone, between 13 and 39 percent survive for five years or more [2].

Postoperative radiation therapy — Radiation therapy is sometimes recommended in patients with stage II NSCLC who have been treated with surgery. When used in conjunction with another treatment, it is called "adjuvant" radiation therapy. Adjuvant RT decreases the chance that a tumor will return or recur following surgery; however, it does not appear to prolong survival [3]. Radiation is more likely to be recommended if small amounts of tumor are thought to remain after surgery, and for those who have substantial involvement of the lymph nodes.

Patients with stage I disease do not appear to benefit from adjuvant RT. In fact, some studies suggest that such treatment actually decreases the chances of survival.

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. However, the bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract are actively growing, and the effects of chemotherapy on these and other normal tissues cause side effects commonly seen during treatment. Most chemotherapy drugs are administered into a vein, although some agents can be given by mouth.

Chemotherapy is most often used for patients with advanced NSCLC (stage IV), although it may be considered for those with earlier stage disease.

Adjuvant (postoperative) chemotherapy — Although patients with early stage NSCLC (stage I or II) do not have any evidence of distant spread when they are diagnosed, they are at risk to develop further cancer spread even after the cancer is surgically removed. It is believed that, in many patients with early stage NSCLC, the cancer cells have spread through the body by the time the lung cancer is detected, even if distant spread cannot be found on x-rays. Thus, using a body-wide treatment such as chemotherapy in an effort to eliminate these undetected cells is reasonable.

Multiple large clinical trials have demonstrated that adjuvant chemotherapy with a cisplatin-based regimen improved five-year survival following resection of NSCLC in patients with stage II, III, and possibly IB disease. There is no evidence to support a benefit in patients with stage IA disease [4].

Based upon these data most physicians recommend that adjuvant cisplatin-based chemotherapy be offered to all patients following surgical removal of stage II or IIIA NSCLC. For patients with stage IB disease the data are conflicting, although studies suggests a small survival advantage for adjuvant chemotherapy.

PANCOAST TUMORS — The term Pancoast tumor (also called superior sulcus tumor) refers to a locally advanced NSCLC that is located in the top part or apex of one of the lungs, in a region called the superior sulcus. Because of their location, these tumors cause a unique set of symptoms including shoulder and arm pain, weakness of the muscles of the hand, and a droopy eyelid associated with flushing or excessive sweating on one side of the face (called Horner's syndrome); this constellation of symptoms is referred to as Pancoast's syndrome. Cough and shortness of breath are less common in Pancoast's sydrome than with lung cancers in other locations.

Superior sulcus tumors are staged in the same way as NSCLCs located elsewhere in the thorax. They usually fall into the category of stage IIB disease (T3,N0), but can also be more advanced (ie, stage IIIA [T3,N1-2], or IIIB [T4] disease, show table 1).

As a group, these tumors may have a better outcome as compared to NSCLCs in the center of the chest, particularly if there is no involvement of the lymph nodes in the mediastinum. In contrast to treatment of other patients with stage II NSCLC, treatment usually consists of a combination of chemotherapy and radiation followed by surgery, as long as there is no evidence of distant spread. Whenever possible, patients with superior sulcus tumors should be enrolled in prospective clinical trials so that the optimal therapy may be determined.

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)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Mountain, CF. Revisions in the international system for staging lung cancer. Chest 1997; 111:1710.
2. Rowell, NP, Williams, CJ. Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (Medically inoperable) (Cochrane Review). Cochrane Database Syst Rev 2001; 2:CD002935.
3. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Available at www.nccn.org/professionals/physician_gls/default.asp (Accessed 3/7/05).
4. Pignon, JP, Tribodet, H, Scagliotti, GV, et al. Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. J Clin Oncol 2006; 24:366s. (Abstract 7008). Abstract available on line (www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD, accessed on June 7, 2006).

Treatment of early stage (stage I and II) non-small cell lung cancer

Treatment of advanced unresectable, metastatic, and recurrent 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, which tend to behave differently, and are treated differently. This topic review will focus exclusively on NSCLC.

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) (show 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 (show table 1). The stage is an important piece of information as it plays a key role in defining treatment options, particularly surgery. The staging of lung cancer is discussed in detail elsewhere. (See "Patient information: Diagnosis and staging of lung cancer").

Patients with advanced unresectable NSCLC are those for whom the tumor cannot be removed with surgery, usually because the cancer has spread, or metastasized, to locations beyond the chest. These patients are said to have "stage IV" disease (show figure 2). Advanced unresectable NSCLC also includes some patients with stage IIIB disease whose cancer may be confined to the chest, but has progressed to the point where surgical removal is not possible. In some cases, patients with stage III NSCLC may be considered for aggressive approaches that use radiation therapy (RT) and chemotherapy with or without surgery.

The treatment of patients with stage III NSCLC is discussed in detail elsewhere. (See "Patient information: Treatment of locally advanced (stage III) non-small cell lung cancer").

Here we will discuss the management of patients with advanced, metastatic, and recurrent NSCLC. Treatment for advanced NSCLC focuses on slowing the effects of the disease, prolonging survival, diminishing symptoms, and ensuring the patient's comfort; treatment for stage IV disease is not curative. Chemotherapy is the primary form of treatment. Some patients, such as those with a single metastatic lesion to the brain, may also benefit from surgery, while radiation therapy may be used to relieve symptoms related to local tumor growth (ie, shortness of breath due to the tumor pressing on the airway, or a painful area of tumor involvement in a bone).

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, 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 give rise to 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, and 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 of drug administration followed by the waiting period is called one "cycle" of chemotherapy. Other chemotherapy drugs can be administered once weekly, such as gemcitabine (Gemzar®) and vinorelbine (Navelbine®) if the period required before resolution of any effects on normal cells is short.

Benefit of chemotherapy — Patients who receive chemotherapy for advanced unresectable NSCLC generally live longer than those who receive supportive care only (several weeks to months), and they are approximately twice as likely to be alive one year later, compared to those who receive supportive care only. As an example, in one analysis that compared chemotherapy with supportive care in over 1000 patients, those receiving cisplatin (Platinol®-AQ)-based chemotherapy (see below) were more likely to remain alive at 12 months (26 compared with 16 percent) [1]. In addition to this survival benefit, chemotherapy also improves quality of life, despite treatment-related side effects. This is because patients receiving 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 may be given a single chemotherapy agent, or placed on combination therapy in which two or more agents are administered simultaneously. Combination therapy is more effective in treating advanced NSCLC, but is associated with more side effects. Compared to single agent therapy, patients receiving combination therapy are more likely to have a decrease in the size of their cancers (ie, a higher "response rate"), and in some cases they may live longer [2,3].

Paclitaxel plus carboplatin — The potential benefit of combination chemotherapy was illustrated in a clinical trial in which 561 patients with advanced NSCLC were randomly assigned to paclitaxel (Taxol®) alone (single agent therapy) or in combination with carboplatin (Paraplatin®) (combination therapy) [4]. Treatment with two drugs resulted in higher rates of tumor shrinkage (30 versus 17 percent) and a longer time until treatment failure (4.6 versus 2.5 months). However, the average duration of survival (8.8 versus 6.7 months) and the quality of life were similar whether the combination or single agent therapy was given.

Adding bevacizumab — The addition of a third drug, the monoclonal antibody bevacizumab (Avastin®), to the two drug chemotherapy combination of carboplatin and paclitaxel appears to represent a significant advance compared to earlier regimens. Bevacizumab is an antibody (a type of protein) that binds 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 also enhances the antitumor effect of other chemotherapy drugs.

In one clinical trial, the addition of bevacizumab to the standard chemotherapy regimen (carboplatin and paclitaxel) improved the response rate, median survival time, and one and two-year survival rates compared to a group that received identical standard chemotherapy [5]. Currently, bevacizumab is recommended for use only in nonsquamous NSCLC (eg, adenocarcinoma) that is unresectable, locally advanced, recurrent, or metastatic.

The addition of bevacizumab to chemotherapy was well-tolerated by most patients. However, it can cause severe hemorrhage (heavy bleeding) in a small percentage of patients. The rate of life-threatening bleeding was 4.1 percent with the bevacizumab and chemotherapy treatment versus 1 percent with chemotherapy alone. Patients in this study were carefully selected to exclude those who were most likely to have serious complications; bevacizumab is not suitable for all patients. Patients with brain metastases, who cough up blood, or taking warfarin (Coumadin) are not candidates for treatment with bevacizumab because of the increased risk of bleeding.

Is there a best regimen? — The results of the trial adding bevacizumab to carboplatin and paclitaxel suggest that this combination offers the best chance to control the disease and is the preferred regimen if there are no contraindications to the use of bevacizumab [5].

For other patients, a two-drug combination remains an appropriate alternative, as was previously recommended in treatment guidelines [6,7]. Several active drugs are available, including cisplatin, carboplatin, vinorelbine (Navelbine®), etoposide (Toposar®; VePesid®), gemcitabine (Gemzar®), paclitaxel (Taxol®), and docetaxel (Taxotere®). Most commonly, either cisplatin or carboplatin, both of which contain platinum, has been used in combination with one of the other agents.

Non-platinum-containing two-drug combinations also represent an acceptable option, particularly for patients who cannot tolerate cisplatin and carboplatin or who have concerns about toxic effects [6]. Examples of chemotherapy regimens that do not include one of the platinum drugs include gemcitabine plus vinorelbine, gemcitabine plus paclitaxel, gemcitabine plus docetaxel, and paclitaxel plus vinorelbine.

Single-agent treatment may be recommended for patients who desire treatment but are unable to tolerate a two-drug combination regimen, or as second-line treatment in people whose cancers progress while receiving two-drug therapy (see "Recurrent disease" below).

Chemotherapy in elderly patients — Elderly patients need to be managed on an individual basis. Guidelines from the American Society of Clinical Oncology recommended single agent therapy in elderly patients [6]. However, for elderly patients who are in good shape (also known as functional capacity) and have no other serious medical conditions, treatment with a carboplatin-based combination, such as carboplatin and paclitaxel or gemcitabine can be considered.

Functional capacity is often measured with a performance status scale (show table 2) 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. Elderly patients at risk for significant chemotherapy-induced side effects are best treated by single-agent chemotherapy, such as vinorelbine or gemcitabine.

Side effects — As noted above, chemotherapy affects some 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 transient drop in the blood counts due to the effect of chemotherapy on the bone marrow. This typically occurs in the midpoint of the waiting period. During this time, any fever or chills should immediately be reported to the patient's physician because having low blood counts can lower resistance to infection. When patients have a low white blood cell count and fever, they are at the highest risk of a life threatening or fatal infection. Other possible side effects include hair loss, numbness in the fingers and toes, 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. As previously noted, cisplatin may be associated with a number of side effects, including effects on the neurologic system and kidneys. Frail or elderly patients may be better served by regimens that have a more favorable side effect profile, such as single agents or non-platinum combinations [4,8].

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 only 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, 230 patients with advanced NSCLC received one of two treatments [9]: Four courses (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 by x-ray studies Continuous treatment with both paclitaxel and carboplatin until the cancer began to grow again by x-ray studies

Compared to continuous combination therapy, response rates were similar when treatment was limited to 12 weeks (22 versus 24 percent), as was the likelihood of surviving one year (28 versus 34 percent). However, the likelihood of treatment-related neurologic side effects was twice as high in patients who received continuous therapy.

Guidelines for treatment of unresectable NSCLC from ASCO recommend that first-line chemotherapy be limited to four to six cycles in duration for patients with stage IV disease, and discontinued in patients who have no evidence of a response after four cycles [6].

RECURRENT DISEASE — 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. Single agent treatment with either docetaxel (Taxotere®) or pemetrexed (Alimta®) 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 [10].

Erlotinib (Tarceva®) and gefitinib (Iressa®) are targeted chemotherapy agents that block a specific molecule that is functioning abnormally in lung cancer cells. Erlotinib is preferred over gefitinib for second-line treatment of NSCLC since it has been shown to prolong survival in clinical studies. Use of gefitinib has been restricted to patients who started it previously since clinical studies have not demonstrated that it prolongs survival, compared to a placebo.

Because erlotinib targets cancerous and not normal cells, the usual side effects of conventional chemotherapy drugs are avoided. The most common side effects are skin rash and diarrhea. These targeted drugs seem to work best in patients of Asian descent, women, nonsmokers, and in patients who have a specific types of NSCLC called adenocarcinoma and bronchioloalveolar cancer, but there is activity of this agent in all groups of patients.

MANAGEMENT OF BRAIN METASTASES — 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 (called corticosteroids or steroids) are often used to help manage symptoms. Unfortunately, the prognosis for patients who have many 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 tumor followed by radiation therapy of the entire brain can contribute to longer survival and some patients survive beyond five years. 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 surgery) is an alternative to conventional surgery in selected patients and may provide results that are comparable to conventional surgery for some patients. Stereotactic radiosurgery uses high dose radiation in a small area, and does not actually require surgery. 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, although they may be useful to help neurologic recovery in some patients. Radiation therapy of the brain may produce a modest increase in survival. More importantly, it can control headache and seizures.

TREATMENT OF MALIGNANT PLEURAL EFFUSIONS — The term pleural effusion refers to a collection of fluid within the chest that is located in the pleural space, not inside the lung. The pleural space is 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 stage IIIB disease (show table 1).

Treatment of the pleural effusion is sometimes necessary to improve shortness of breath, which often worsens as more fluid accumulates. A summary of the treatment options for malignant pleural effusions is presented here (show table 3).

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. This is followed by instillation of talc in a slurry (a thick mixture of talc and sterile water) into the tube at the bedside. This procedure is called tube thoracostomy. Treatment is performed while the patient is in the hospital. Most patients stay in the hospital for three to five days.

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

Thoracoscopic application of the talc does not appear to provide superior results compared to use of a talc slurry administered via chest tube. However, in one large study specifically designed to compare the two methods of application, quality of life analysis revealed significantly greater comfort and perception of safety in the group treated thoracoscopically, despite a higher number of respiratory complications from the surgery [11].

Indwelling catheter — Some patients are being 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 when needed. Tunneled catheters do not require use of talc and generally have a lower risk of respiratory complications [12]. In many centers, the tunneled catheter is replacing talc pleurodesis as the procedure of choice for treating malignant pleural effusions.

An indwelling catheter is a suitable alternative to the above treatments, and is preferred when the patient is debilitated, has an area of the lung blocked by tumor, which prevents the lung from expanding completely. It may also be preferred if the patient is not expected to live for a long time. It is particularly suitable for patients who want to avoid hospitalization and who are willing to manage the catheter. The catheter can be placed as day surgery procedure. It allows the patient and their clinicians to manage the pleural effusion out of the hospital.

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

1-800-4-CANCER
(www.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)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
Lung Cancer Alliance

(www.lungcanceralliance.org)

[1-4,6-12]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data opn individual patients from 52 randomised clinical trials. BMJ 1995; 311:899.
2. Shanafelt, TD, Loprinzi, C, Marks, R, et al. Are chemotherapy response rates related to treatment-induced survival prolongations in patients with advanced cancer?. J Clin Oncol 2004; 22:1966.
3. Delbaldo, C, Michiels, S, Syz, N, et al. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis. JAMA 2004; 292:470.
4. Lilenbaum, RC, Herndon JE, 2nd, List, MA, et al. Single-Agent Versus Combination Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The Cancer and Leukemia Group B (study 9730). J Clin Oncol 2005; 23:190.
5. Sandler, AB, Gray, R, Brahmer, J, et al. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599 (abstract). J Clin Oncol 2005; 23:2s. Abstract available online: (www.asco.org/portal/site/ASCO/ accessed on March 2, 2007).
6. Pfister, DG, Johnson, DH, Azzoli, CG, et al. American society of clinical oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004; 22:330. Also available online at www.jco.org/cgi/content/full/22/2/330.
7. National Comprehensive Cancer Network. Treatment guidelines for patients. Available at www.nccn.org/patients/patient_gls.asp (Accessed 5/12/06).
8. Gridelli, C, Perrone, F, Gallo, C, et al. Chemotherapy for Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) Phase III Randomized Trial. J Natl Cancer Inst 2003; 95:362.
9. Socinski, MA, Schell, MJ, Peterman, A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002; 20:1335.
10. Hanna, N, Shepherd, FA, Fossella, FV, et al. Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy. J Clin Oncol 2004; 22:1589.
11. Dresler, CM, Olak, J, Herndon JE, 2nd, et al. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest 2005; 127:909.
12. Tremblay, A, Michaud, G. Single-center experience with 250 tunnelled pleural catheter insertions for malignan

Treatment of advanced unresectable, metastatic, and recurrent non-small cell lung cancer

Lung cancer prevention and screening

INTRODUCTION — Lung cancer is the leading cause of cancer death in both men and women in the United States. The number of people dying from lung cancer each year has risen over the past 25 years. It is estimated that lung cancer will be responsible for approximately 160,000 deaths in the US during 2006. This is more than the estimated deaths from breast cancer, prostate cancer, and colorectal cancer combined. Several factors increase the risk of lung cancer, particularly cigarette smoking.

PREVENTING LUNG CANCER — Cigarette smoking is responsible for almost 90 percent of cases of lung cancer. Exposure to certain substances, such as asbestos, has also been linked to the development of lung cancer. Exposure to second-hand smoke and other environmental factors may play a role.

The best way to avoid getting lung cancer is not to smoke. Some smokers believe that once they have smoked for a long while, it does little good to quit. However, studies have shown that smokers who quit decrease their risk of lung cancer when compared to those who continue to smoke. Smokers who quit for more than 15 years have an 80 to 90 percent reduction in their risk of lung cancer compared to people who continue to smoke. (See "Patient information: Smoking cessation").

IS SCREENING WORTHWHILE? — Screening is a way to detect a disease in its earliest stages, before a person becomes ill or dies. To be recommended, it must be clear that screening is useful in identifying patients who have the disease in the early stages, and that this discovery can reduce the number of patients who become ill and/or die.

Some screening exams have proven to make a clear difference in patient outcomes. Examples are the Pap smear for detection of cervical cancer in women, and colonoscopy for detection of colon or rectal cancer in people over 50 years old. These exams are now part of routine health care in the United States.

SCREENING EXAMS FOR LUNG CANCER — Research studies have been done to determine if screening for lung cancer makes sense. In these studies, smokers (who are at highest risk to develop the disease) are divided into groups. Some groups have screening tests while others have no screening. The groups are then followed over many years. Data are gathered on how many patients in each group are diagnosed with lung cancer, how the cancer was treated, and how long patients with lung cancer survived after treatment.

So far, the data from these studies have not shown that screening for lung cancer makes a difference in deaths from the disease. For this reason, major medical advisory groups do not yet recommend lung cancer screening.

Still, the data from these studies are the subject of much debate in the medical community. Part of the debate surrounds the fact that outcomes other than overall mortality, such as the stage of the disease at diagnosis or five-year survival rate, seem to be favorably affected by screening. However, critics point out that data are difficult to interpret reliably. The debate is continuing, and more studies are underway to better understand the role of screening studies for lung cancer

Because of the lack of data on the efficacy of screening for lung cancer, most of these exams are not part of routine care and are only offered to smokers as part of ongoing clinical trials. One exception may be the annual chest x-ray.

Chest x-ray — Many doctors already recommend an annual chest x-ray for their patients who smoke. Some experts, in analyzing data from lung cancer screening trials, have concluded that an annual chest x-ray is a worthwhile screening exam for patients with lung cancer.

Two major studies have been done to find out whether more frequent chest x-rays are beneficial in lung cancer screening. So far, these studies have not shown a clear benefit in terms of deaths from lung cancer. In patients who had more frequent chest x-rays, more lung cancers at early stages were found, the cancers were more frequently removable by surgery, and the patients had longer five-year survival (from time of diagnosis) than patients with less frequent x-rays. However, overall mortality from lung cancer was not significantly affected.

Computed tomography (CT scan) — Studies of computed tomography (CT scan) of the lung have shown that the test can help detect early stage lung cancer, but it is not yet clear whether this will affect the number of patients who die from their cancer.

Sputum tests — Some studies have looked at the efficacy of analyzing a patient's sputum for evidence of cancer cells in order to detect lung cancer. So far, no clear benefit to this approach has been found. Additional studies that use new technologies to examine the sputum are underway.

PET scan — Researchers are looking at a number of other tools in an effort to help identify patients with lung cancer. Positron Emission Tomography (or PET scanning, which uses a small amount of radioactivity to provide a detailed picture of an organ's function) has been used in combination with CT scanning.

Other studies — Direct visualization of the lungs with bronchoscopy and breath analysis for cancer markers are two tests that may be used in future studies.

CLINICAL TRIALS — Because the data on lung cancer screening are inconclusive, large-scale clinical trials of various screening modalities are underway. Smokers or former smokers may be asked to participate in these trials.

Although it makes sense to think that early detection of lung cancer is a good idea, it is important to understand that routine screening for lung cancer cannot be recommended until the research clearly shows that it makes a difference. It is likely that recommendations on lung cancer screening will evolve over the next decades as these data become available.

SUMMARY Patients who smoke are at increased risk of developing lung cancer. The best way to avoid lung cancer is not to smoke. Even long-term smokers can benefit from quitting. Researchers are looking for ways to help smokers and non-smokers who develop lung cancer to live longer. Early detection and screening is a major focus of this effort It is not clear if lung cancer screening can reduce the number of people who die from their disease. Clinical trials are underway that will help provide answers to these questions.

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)

[1-4]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2006. CA Cancer J Clin 2007; 57:43.
2. Truong, MT, Munden, RF. Lung cancer screening. Curr Oncol Rep 2003; 5:309.
3. Nawa, T, Nakagawa, T, Kusano, S, et al. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002; 122:15.
4. Bastarrika, G, Garcia-Velloso, MJ, Lozano, MD, et al. Early Lung Cancer Detection using Spiral Computed Tomography and Positron Emission Tomography. Am J Respir Crit Care Med 2005; 171:1378.

Pages

Friday, October 12, 2007

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

Treatment of early stage (stage I and II) non-small cell lung cancer

Treatment of early stage (stage I and II) non-small cell lung cancer

Treatment of advanced unresectable, metastatic, and recurrent non-small cell lung cancer

Treatment of advanced unresectable, metastatic, and recurrent non-small cell lung cancer

Lung cancer prevention and screening