Authored by: Bryan J. Schneider, M.D. and Gregory P. Kalemkerian, M.D. Division of Hematology/Oncology, Department of Internal Medicine University of Michigan, Ann Arbor, MI 48109-0848 INTRODUCTION Lung cancer is the leading cause of cancer-related death in the United States for both men and women. In the United States, 80% of patients with lung cancer have non-small cell lung cancer, while the remaining 20% have small cell lung cancer. Non-small cell lung cancer is a "catch all" term for a group of cancers originating in the lung that includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. All of these diseases are treated in a similar fashion, and are therefore discussed under the general heading of non-small cell lung cancer. The average age at diagnosis of lung cancer is 68 years, which means that more than half of all patients with non-small cell lung cancer are older than 65 years of age and one-third are over 70 years old. WHAT DOES “ELDERLY” MEAN? Prior to making treatment recommendations, the oncologist must assess an individual patient's ability to tolerate the various types of treatment that are available to treat cancer, including surgery, radiation therapy, and chemotherapy, used either alone or in combination with each other. Patient age must be considered because some treatments may not be tolerated as well by older patients as by younger individuals. In previous studies, the definition of an "elderly" patient has varied from 65 years of age or older to 75 years of age or older. A more functional definition of "elderly" has been proposed as follows:"when the health status of a patient begins to interfere with oncological (cancer) decision-making guidelines"(1). This definition also takes into account the fact that a patient's other medical problems could interfere with treatment of the cancer. Age, by itself, does not generally prevent the use of the best available therapy. However, with increasing age comes a higher propensity for chronic illnesses that may impair a patient's functional ability and alter his or her ability to tolerate aggressive anticancer treatment. Debility caused by the cancer or by other illnesses may change the balance between the potential risks and benefits of a specific treatment. Another relevant issue is that although lung cancer is very common in elderly patients, most of the available data regarding the optimal treatment of lung cancer comes from clinical trials in which the vast majority of patients are significantly younger than 65 years of age. Few elderly patients are enrolled into clinical trials, perhaps due to the greater chance that they may have other medical problems that exclude them from a trial or due to potential bias on the part of their physicians or the elderly patients themselves against enrollment in trials studying investigational, and potentially more aggressive, therapies. It is only in the past 10 years that trials have been specifically designed to evaluate the potential benefits and risks of treatment in elderly patients, but even in clinical trials designed for patients 70 years of age or older, the average age of treated patients tends to be in the early 70s with few patients over the age of 80 participating in such trials. CHOOSING TREATMENT Two of the most important pieces of information needed to decide on the appropriate treatment for patients with non-small lung cancer are the stage of the disease and the performance status of the patient. Cancer staging is a way to describe the extent of the disease. It also helps the oncologist guide treatment decision-making and offer general information to the patient regarding overall prognosis. In non-small cell lung cancer, staging is done by looking at the size of the tumor, involvement of lymph nodes within the chest, and the presence of cancer spread to areas outside of the chest, such as the brain, liver, bones, or adrenal glands. Table 1 presents the most common staging system used by oncologists for patients with non-small cell lung cancer(2).  The performance status of a patient helps an oncologist define how the lung cancer or other medical problems are affecting the patient's ability to function. The worse the performance status, the more likely it is that the patient will have significant complications during aggressive treatment. Table 2 presents one performance status scale commonly used by oncologists to gauge an individual patient's level of daily functioning. Patients with non-small cell lung cancer and a performance status of 3 or 4 are usually not candidates for surgery or chemotherapy. In addition to evaluating general performance status, a careful assessment of heart function, lung function, and other chronic illnesses may be required before treatment recommendations can be made.  TREATMENT OF PATIENTS WITH STAGE I OR STAGE II DISEASE SURGERY Stage I or II non-small cell lung cancer typically means that the cancer is confined to the lung and there is no or minimal lymph node involvement. The most effective treatment for patients with stage I or II disease is to surgically remove the cancer by cutting out all or part of the involved lung. Studies have shown that elderly patients with good lung and heart function and a good performance status can tolerate lung cancer surgery as well as younger patients with a similar chance for cure (3-7). Older patients may need to undergo a more rigorous evaluation of their heart and lung function prior to surgery to ensure that surgery can be performed safely and with an acceptable risk of long-term complications. For patients with stage I disease, 60-80% can be cured by surgical removal of the cancer. For those with stage II disease, 40-50% of patients can be cured by surgery. For more information on surgery, see the article in CancerNews titled "Lung Cancer: Who is a Candidate for Surgery?" RADIATION THERAPY Radiation therapy is the treatment of cancer by a beam of high energy x-rays directed at the part of the body affected by the cancer. Like surgery, it is a local treatment that only can kill cancer cells within the area being treated, not throughout the whole body. Some elderly patients may not be able to undergo surgical removal of stage I or II non-small cell lung cancer because of a significant medical problem, such as a recent heart attack or poor lung function due to emphysema. In these situations, radiation therapy targeted to the main lung tumor and to lymph nodes to which the cancer has spread may be the best treatment option for potential cure. However, the chance for cure in patients with stage I disease treated with radiation therapy is only 20-30%, significantly lower than that seen with surgery (8). For patients who can tolerate surgery and undergo complete removal of a stage I or II cancer, radiation therapy is not typically recommended because it has not been shown to improve the chance for cure and can cause potentially serious side-effects in patients with underlying lung disease. CHEMOTHERAPY Chemotherapy is a term that pertains to many different drugs, usually given through a vein, used to try to kill cancer cells wherever they might be in a patient's body. Chemotherapy is not typically used as the sole treatment for stage I or II non-small cell lung cancer because by itself it cannot cure the disease. Sometimes it is used after surgery as adjuvant therapy (meaning "in addition to" the primary treatment, in this case surgery). In several recent clinical trials, chemotherapy has been shown to decrease the chance for cancer recurrence and improve the chance for cure in some patients who have undergone complete surgical removal of stage IB, II, or IIIA non-small cell lung cancer. All of these studies were randomized trials in which half of the enrolled patients received chemotherapy after surgical removal of the tumor and the other half received no further therapy. The first of these adjuvant trials, called IALT, demonstrated a 5% decrease in cancer recurrence rate and a 4% improvement in survival in patients treated with cisplatin-based chemotherapy compared to those receiving no further therapy after surgical removal of stage IB, II, or III non-small cell lung cancer (9). While the benefit of chemotherapy in this trial may seem small, a recurrence of the cancer is usually incurable, meaning that chemotherapy given after surgery can prevent some people from dying of the cancer. Importantly, patients over 75 years of age were not allowed to participate in this trial and the average age of patients enrolled was only 59 years. Therefore, it is not clear whether the benefit of chemotherapy seen in this trial would also occur in an older population of patients. The second of these trials, called JBR.10, demonstrated a 15% improvement in survival in patients treated with the chemotherapy combination of cisplatin plus vinorelbine compared to those receiving no further therapy after surgical removal of stage IB or II non-small cell lung cancer (10). The third recent adjuvant chemotherapy trial, called CALGB 9633, demonstrated a 12% improvement in survival in patients treated with carboplatin plus paclitaxel compared to those receiving no further therapy after surgical removal of stage IB non-small cell lung cancer (11). Although the JBR.10 and CALGB 9633 trials did not limit the age of potential participants, the average age of patients enrolled in both of these trials was 61 years and few patients were over 75 years of age. The most recent of the adjuvant trials, called the ANITA trial, demonstrated an 8% improvement in survival in patients treated with cisplatin plus vinorelbine compared to those receiving no further therapy after surgical removal of stage IB, II, or IIIA non-small cell lung cancer (11). As in the first trial mentioned above, patients over the age of 75 years were not allowed to participate in the ANITA trial. Overall, adjuvant chemotherapy is now recommended for patients who have undergone complete removal of stage IB, II, or III non-small cell lung cancer and have recovered from surgery within two months without significant complications. Clearly, the oncologist must carefully evaluate every patient to ensure that the potential benefits of chemotherapy outweigh the risk of serious side-effects of treatment. If adjuvant chemotherapy is given, the chemotherapy should consist of four cycles of cisplatin or carboplatin in combination with another chemotherapy agent, usually vinorelbine, paclitaxel, or etoposide. While age alone should not be a deterrent to receiving adjuvant chemotherapy, the oncologist must keep in mind that very few elderly patients were involved in the clinical trials that determined the benefits of this treatment. TREATMENT OF PATIENTS WITH STAGE III DISEASE Stage III disease usually means that the cancer has directly extended outside the lung into other structures within the chest or has spread to the lymph nodes outside of the lung within the middle of the chest, called the mediastinum. The mediastinum is the area in the chest between the lungs where the heart, major blood vessels, esophagus, and windpipe are located. Unfortunately, stage III non-small cell lung cancer is more difficult to cure than earlier stage disease. Surgery is usually not an option due to the extent of disease and its proximity to vital organs. Most patients with stage III disease are treated with a combination of radiation therapy and chemotherapy. However, the particular type of treatment recommended for an individual patient is dependant on his or her performance status, degree of prior weight loss, and overall medical condition. For patients with significant functional impairment, radiation therapy alone may be recommended. Although the chance for cure with radiation alone is small (13), the addition of chemotherapy may add an unacceptable risk of side-effects and further debility in these patients. Patients who are able to care for themselves, but require some assistance, or who have had significant weight loss may be candidates for chemotherapy followed by radiation therapy. This sequential form of chemotherapy and radiotherapy offers a better chance for cure than radiation therapy alone, but also introduces potential side-effects from chemotherapy. Patients who are in good physical condition and have had minimal weight loss, may be candidates for radiation therapy and chemotherapy given together at the same time. This treatment offers the best chance for cure, with 15-20% of patients alive 5 years after the diagnosis (14, 15). However, concurrent radiation and chemotherapy is also associated with greater short-term and long-term side-effects that may not be tolerated by patients who are frail, have had significant weight loss, or have other major medical problems. There are several acceptable ways of combining chemotherapy and radiation therapy, but the optimal method has not yet been defined. Radiation is typically administered once a day, Monday though Friday, for 6 weeks. Chemotherapy can be given as two cycles of intermittent treatment with combinations of drugs such as cisplatin plus etoposide or carboplatin plus etoposide, or treatment once a week during radiation therapy with a combination such as carboplatin plus paclitaxel. The combination of carboplatin plus etoposide probably offers the most tolerable risk of side-effects (16). The common side-effects of concurrent chemotherapy plus radiation therapy include fatigue, drops in the blood counts that can increase the risk of infection or bleeding, irritation of the esophagus that can cause difficulty swallowing, and inflammation of the lungs that can cause cough or shortness of breath. No clinical trials have yet been designed to specifically study the treatment of elderly patients with stage III non-small cell lung cancer. Some trials that included both young and elderly patients have compared the effects of the treatment on elderly patients versus the younger ones. One such analysis was done of a trial comparing sequential to concurrent chemotherapy plus radiation therapy (17). All patients enrolled in this trial had a good performance status, but only 17% were elderly (70 years old or older). The elderly patients on this trial were just as likely to complete treatment and obtained as much benefit from treatment as younger patients. Although the elderly patients had a higher risk of short-term side-effects, specifically low blood counts and esophageal irritation, they did not have any greater risk of long-term complications. Another analysis was done of a study comparing chemotherapy plus concurrent chemotherapy given once or twice a day in which 26% of patients were 70 years old or older (18). Again, the chance for cure was similar in younger and elderly patients, but the risks of side-effects, particularly low blood counts and inflammation of the lungs, was higher in elderly patients. Overall, these data suggest that concurrent chemotherapy plus radiotherapy is both tolerable and beneficial in elderly patients with stage III non-small cell lung cancer who are in good overall physical condition. TREATMENT OF PATIENTS WITH STAGE IV DISEASE Stage IV disease usually means that the cancer has spread through the bloodstream to another location in the body, either to the other lung or to organs outside of the chest such as the brain, liver, adrenal glands, or bones. Unfortunately, stage IV non-small cell lung cancer is not curable with any currently known treatments. Surgery and radiation therapy are local treatments that cannot eradicate cancer once it has spread to a distant site. Therefore, the primary treatment option for patients with stage IV disease is chemotherapy, and the goal of treatment is to prolong good quality of life. Standard treatment consists of a combination of two chemotherapy drugs, usually cisplatin or carboplatin plus another agent such as paclitaxel, gemcitabine, docetaxel or vinorelbine. The use of cisplatin in elderly patients may result in a greater risk because of its particular side-effects which include impairment of kidney function, damage to the nerves in the hands and feet, nausea and vomiting with resultant dehydration, and hearing loss. Cisplatin should clearly be avoided in elderly patients that already have, or are at specific risk for, one of these conditions. Despite these concerns, analyses of two studies that treated patients of all ages with a cisplatin-containing regimen have shown that ¡°fit¡± elderly patients with a good performance status had no significant differences in response to treatment or survival when compared to the younger patients on the trials (19,20). Several studies have specifically studied the use of chemotherapy in elderly patients with advanced non-small cell lung cancer. One of the central questions of these studies has been the potential role of single-drug treatment based on the rationale that one drug would result in fewer side-effects than combinations of chemotherapy drugs, and may therefore lead to improved quality of life and duration of survival in the elderly population (21-24). The ELVIS trial randomized patients age 70 years or older to receive either vinorelbine or no chemotherapy (21). Patients receiving vinorelbine reported better quality of life and were found to have longer survival than those who received no chemotherapy. A second trial, the MILES trial, compared two different types of single-drug therapy, gemcitabine or vinorelbine, against the combination of the two drugs given together in patients 70 years of age or older with advanced non-small cell lung cancer (22). Treatment with the combination of drugs did not improve patient survival or quality of life, but was associated with a greater risk of significant side-effects. Overall, while it appears that ¡°fit¡± elderly patients can tolerate and may benefit from treatment with a combination of chemotherapy agents, there is little data to suggest that such combinations of drugs offer any benefit over single-drug chemotherapy in the elderly patient population. Recently, newer drugs that can more specifically target lung cancer cells have been developed and have been shown to benefit some patients with advanced non-small cell lung cancer. In general, these drugs have more tolerable side-effects than standard chemotherapy since they are more specifically aimed at the cancer cells. Erlotinib is one such drug that has been approved for use in patients with advanced non-small cell lung cancer. Erlotinib is a pill that can result in tumor shrinkage and improvement in duration of survival in patients with non-small cell lung cancer that has recurred after initial treatment with standard chemotherapy (25). To date, specific studies of erlotinib in elderly patients have not been reported, and the drug does have potential side-effects, such as diarrhea, that may be particularly problematic in the elderly population. Thus far, we know that women, non-smokers, people of East Asian heritage, and those with adenocarcinoma seem to benefit the most from treatment with erlotinib (26). As stated earlier, radiation therapy cannot treat all sites of disease in patients with advanced non-small cell lung cancer, but it can be very useful in alleviating distressing symptoms, such as pain due to bone invasion or cough and shortness of breath due to the obstruction of an airway. In addition, radiation therapy is the primary treatment for patients with cancer that has spread to the brain. Finally, some elderly patients with advanced, incurable non-small cell lung cancer may elect not to undergo therapy because of the potential for serious side-effects. This is certainly a reasonable option, and support services such as hospice care can aggressively treat symptoms and work to improve quality of life, with the goal of keeping patients functional and feeling well for as long as possible. Hospice care can offer much needed assistance for both the patient and their family in dealing with the physical, emotional, spiritual, and practical aspects of living with a terminal disease. CONCLUSION In the past, elderly patients were frequently not offered standard treatment for lung cancer purely based on their age and the concern that they would not be able to tolerate therapy. While this may be the case in a fair number of elderly patients who have significant limitations in their functional ability or other medical illnesses, it has now become clear that many elderly patients can tolerate and benefit from standard treatments for lung cancer. In recent years, there has been a greater focus on the development of clinical trials that specifically address lung cancer treatment in the elderly and several excellent reviews of this topic have been published in the medical literature (27-31). It is important to stress that performance status is the most significant indicator of how well an individual patient will tolerate therapy and how well they will do with the disease in general. Patients with a limited performance status have a shorter survival time and are much less likely to benefit from treatment. However, "fit" elderly patients with a good performance status may be good candidates for standard therapy, and may gain just as much benefit from such therapy as younger patients. |
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