Friday, October 12, 2007

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)


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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

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