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.

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