As half of all breast cancers occur in patients beyond the age of 65 and a quarter beyond the age of 75, a significant number of patients with metastatic breast cancer are elderly. New hormonal therapies, such as aromatase inhibitors, appear to have favorably improved the survival of these patients. Side effects such as osteoporosis or cognitive issues appear manageable. Information specific to elderly patients has recently emerged in the field of chemotherapy for metastatic breast cancer. This article reviews data on anthracyclines, taxanes, capecitabine (Xeloda), gemcitabine (Gemzar), trastuzumab (Herceptin), and bevacizumab (Avastin). For most patients in this setting, sequential single-agent chemotherapy appears at this time to be the preferred course of treatment.
As life expectancy in the United States has increased, and the health of the older population has improved, the number of older women with breast cancer who are eligible for treatment for either early- or late-stage disease has also increased. This change has paralleled improving supportive care, and an enlarging array of treatment options. The article by Extermann outlines treatment approaches for older women with metastatic breast cancer who have either hormone-insensitive or resistant disease. Although a minority of older women have hormone-receptor-negative disease at diagnosis, all women will eventually develop resistance to all available hormone therapies and therefore be potentially eligible for chemotherapy to treat advanced disease.
Benefits vs Risks
Older women are more likely to have competing morbidities that increase toxicity and potentially reduce benefit from available treatment options. However, as Dr. Extermann describes, there are a number of single-agent chemotherapy options that are relatively well tolerated by even the very elderly. Decisions to continue treatment at evidence of progression for women of any age with advanced disease should consider quality of life, toxicities, and relative benefits vs risks of the treatment options, and of course include a discussion with the patient and her family about the goals of treatment.
A variety of single-agent chemotherapeutic agents are very well tolerated by elderly women, and can provide both prolonged survival and improvement in disease-related symptoms. Therefore, understanding the unique toxicities that could be of greater concern in the older population is increasingly important, and critical to both choice of therapy and appropriate counseling. Unfortunately, little data exists to guide choice of therapy. Extermann outlines available small phase II studies evaluating a variety of chemotherapy agents in older women, and reviews the available toxicity data.
Should we offer elderly women chemotherapy? First, it is important to understand that that definition of the 'older woman' is highly variable depending on the trial, many including women over the age of 60, and very few examining the population of women who might reasonably be called elderly-those over 70. Clinical trials generally exclude women who are most similar to those we see in practice, those with a variety of medical problems and on a variety of medications. Nonetheless, many women in their 70s and often much older enjoy an excellent performance status, and are motivated to try therapies in the metastatic setting that might prolong life with reasonable quality.
What are the best options? Single-agent chemotherapy is effective, and in all trials associated with less toxicity than combination regimens. Capecitabine (Xeloda) offers the advantage of less frequent visits and oral dosing, but the complication of compliance and toxicity issues. Older women should be carefully counseled as to management of toxicity and should be encouraged to use a medication box to ensure correct dosing and schedule. One approach that is often well tolerated is a 1-week-on, 1-week-off schedule. This approach is being investigated in clinical trials as well. Dr. Extermann points out that the maximum dose of capecitabine should be 2,000 mg/m2 per day in two divided doses, with a low threshold for dose reduction in response to toxicity.
Schedule of Administration
Toxicity of chemotherapeutic agents is clearly modulated by changes in schedule of administration. In general, paclitaxel given weekly and docetaxel given every 3 weeks are the most tolerable and effective schedules for these taxanes. Docetaxel doses should be reduced in the older population to avoid excessive hematologic toxicity. The new nano-particle paclitaxel, nab-paclitaxel (Abraxane), offers an attractive alternative as it can be given quickly and does not require premedications, therefore avoiding the toxicity of steroids. In addition, the sensory neuropathy associated with nabpaclitaxel appears to resolve quickly and improves with dose reduction. The best schedule in an older patient is weekly, giving two or three doses in a row followed by a 1-week rest.
Weekly anthracyclines (particularly epirubicin [Ellence]) appear to be well tolerated, although as Extermann explains, older patients will be at higher risk for cardiac toxicity and require close monitoring as well as possibly the addition of dexrazoxane. Gemcitabine (Gemzar) at 1,000 mg/m2 given in a 2-weeks-on, 1-week-off schedule is usually well tolerated, but older patients may suffer from severe fatigue, limiting use of this agent. Lower doses may improve this symptom as well as hematologic toxicity. Vinorelbine should be used with caution in the older population, with careful monitoring for hematologic and gastrointestinal toxicity (primarily ileus) as well as cumulative sensory neuropathy. Dose reductions and intermittent scheduling improve tolerance.
What about targeted therapeutics? Bevacizumab (Avastin) is expected to be approved for the treatment of metastatic breast cancer given in combination with paclitaxel in the future. The older population is more likely to have hypertension on medications, or to have modest renal insufficiency, potentially increasing the risk of toxicities commonly seen with antiangiogenic therapy. Blood pressure and urine protein levels should be monitored before each dose. If blood pressure is controlled, it is reasonable to combine bevacizumab with a taxane or potentially with other agents as first-line therapy for metastatic breast cancer even in the elderly.
HER2 overexpression is seen in only a small number of breast cancers arising in older women. However, trastuzumab (Herceptin) is as likely to benefit older women as their younger counterparts and should be part of the therapy offered in this setting. In an older population, it is even more critical to evaluate baseline cardiac function and follow this serially during treatment. Risk factors for trastuzumab cardiac toxicity, including prior cardiac events, are more likely to occur in the older population but do not preclude therapy.
The new oral tyrosine kinase inhibitors (TKIs) are more problematic due to cost (and lack of adequate coverage for oral medications in the Medicare population). Results of a study recently presented at ASCO demonstrated a significant improvement in progression-free survival when a new oral TKI targeting HER2 and HER1 (EGFR)-lapatanib (Tykerb)-was combined with capecitabine, compared to treatment with capecitabine alone in women with trastuzumab-resistant advanced breast cancer. Lapatanib is well tolerated and may have less cardiac toxicity than trastuzumab. Planned clinical trials will compare each agent and the combination in early- and late-stage disease. This may be an effective treatment option for older women, providing insurance coverage is available.
-Hope S. Rugo, MD
Dr. Rugo receives research support through UCSF from Genentech and GlaxoSmithKline, and future research support from Bristol-Myers Squibb and Abraxis is planned.
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