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.
The focus of this well-organized review outlining treatment options for older women diagnosed with breast cancer is threefold, addressing hormonal therapy, chemotherapy, and targeted agents. Upfront, Dr. Extermann appropriately discusses the biologic differences noted in breast cancers at the extremes of age. In general, a breast cancer in a younger woman is more likely to have aggressive features than a breast cancer in an older woman,[1,2] but, as aptly pointed out by the author, this is not always the case. The approach to treating metastatic breast cancer, therefore, should be based on the tumor and the patient.
A common and essential theme weaves its way throughout this article-metastatic breast cancer is an incurable disease. The job of every oncologist is to prolong life, where possible, and to decrease suffering. Appropriately, each section of this review focuses not only on the benefits of therapy, but also on the risks involved.
We would like to emphasize the importance of hormonal therapy for metastatic breast cancer-this modality should always be the initial therapeutic consideration, regardless of age. Dr. Extermann's lack of emphasis on this topic probably results from the lack of published data regarding age-related differences in outcomes and toxicities, because these agents are generally well tolerated and extremely effective for hormone-receptor-positive metastatic breast cancer.
For decades, the selective estrogen-receptor modulator (SERM) tamoxifen was the cornerstone of hormonal therapy for women with breast cancer, in both the adjuvant and metastatic setting. More recently, aromatase inhibitors (AIs) moved to the forefront of treatment for postmenopausal women with advanced breast cancer and are now indicated as first-line treatment. Trials comparing the AIs to tamoxifen show a benefit of AIs with regard to response rate and time to progression in the metastatic setting.[3,4]
Although venous thromboembolism and endometrial cancer are less of a consideration with AIs than they are with SERMs, osteoporosis, fractures, arthalgias, and mild cognitive impairment can occur.[5,6] These AI side effects, as Extermann points out, may be important to the elderly patient. In our opinion, however, the benefit of response or stable disease in metastatic breast cancer far outweighs the long-term risk of osteoporosis and the side effects of arthralgias/myalgias and cognitive impairment.
In addition, a woman who has a documented response (lasting 4 to 6 months or longer) to one form of hormonal therapy for metastatic breast cancer should be offered second-, third-, and even fourth-line hormonal therapy, as other effective hormonal therapies are available and continued responses are seen. Options include another non-cross-resistant AI, fulvestrant (Faslodex), megestrol acetate, and high-dose estrogens, among others. New approaches with agents that may reverse resistance to hormonal therapy or more effective new single agents or combinations are under investigation.
Dr. Extermann does a superb job of reviewing the growing literature regarding pharmacology of chemotherapy agents in older women with breast cancer. Important side effects that make us more wary when treating older patients include cardiotoxicity, as is associated with cumulative doses of anthracycline, mucositis, and neurotoxicity. Polypharmacy, however, is a particularly important issue in older patients, as many in this population are on multiple medications. Docetaxel, for instance, is entirely metabolized by the cytochrome P450 subenzyme CYP3A4 pathway, and is prone to interaction with other medications. These interactions can lead to higher or lower levels of drug than expected, thus translating into increased toxicity or decreased efficacy.
Targeted agents, such as trastuzumab (Herceptin) and bevacizumab (Avastin), show great promise in treating metastatic breast cancer and there is little data on how their side effects and efficacy may vary with age. For now, we employ them with caution in the very old, as they are rarely included in trials of new drugs for metastatic breast cancer.[7-9]
Regardless of age, therapy for metastatic breast cancer is palliative and should be individualized based on the urgency of the clinical presentation and the desires of the patient. Hormonal therapy is recommended as initial treatment and should be continued until the disease is clearly hormone-refractory. Trastuzumab should be used to treat tumors that express HER2. Other treatments should be added based on the therapeutic profile of the agent and the goals of therapy chosen by the patient and the provider. We look forward to more clinical trial data to guide the treatment of older patients.
-Carey K. Anders, MD
-Gretchen Kimmick, MD, MS
Dr. Kimmick is a member of the speakers bureau and advisory board for AstraZeneca, and is a member of the speakers bureau for Pfizer.
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5. Baum M, Buzdar A, Cuzick J, et al, for the ATAC Trialists' Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of post-menopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003.
6. Jenkins V, Shilling V, Fallowfield L, et al: Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 13:61-66, 2004.
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9. Miller KD, Wang M, Gralow J, et al: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: A trial coordinated by the Eastern Cooperative Oncology Group (E2100) (abstract 3). Breast Cancer Res Treat 94(suppl 1):S6, 2005.