Chemotherapy

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The role of adjuvant chemotherapy in older women is controversial. Although earlier trials showed minimal benefit in older women, recent larger trials and the Oxford overview analyses have revealed that adjuvant chemotherapy results in modest benefits in postmenopausal women (Table 33.9). In the most recently published overview analysis, there were too few women in the 70 and older age group to draw conclusions about chemotherapy in this population, and few randomized trials have included many women over 70 years of age. Among women aged 50 to 69 years, chemotherapy for women with estrogen receptor-negative tumors resulted in a reduction in the risk of recurrence of 30% (±5%) compared to a reduction of 40% (±7%) in women less than 50 years of age. For women with estrogen receptor-positive tumors who will also benefit from tamoxifen, chemotherapy resulted in a decrease in the risk of recurrence of 18% (±4%) among women aged 50 to 69 years compared to 33% (±8%) proportional risk reduction in women less than 50 years of age.

An important question for older women with ER- positive tumors is whether adjuvant chemotherapy adds anything to the benefits of tamoxifen. The overview analysis, as well as individual studies, have demonstrated that combination therapy with tamoxifen and chemotherapy is better than the use of either treatment alone in women with estrogen receptor-positive tumors.

In the overview, combination therapy resulted in an overall reduction in the risk of both recurrence and death of 19% (±3%) and 11% (±4%), respectively, among women aged 50 to 69 compared to tamoxifen alone. Because the benefits of chemotherapy appear to decrease with age, however, the absolute incremental benefit of chemotherapy added to tamoxifen in older women with hormone receptor-positive tumors may be relatively small. In women with ER-positive disease of all ages, combination chemotherapy and tamoxifen resulted in a reduction in risk of recurrence and death of 52% (±8%) and 47% (±9%) respectively, compared to chemotherapy alone. The overview analysis also suggested that anthracycline-containing chemotherapy regimens are superior to non-anthracycline-containing regimens. However, concern about the inherent risk of cardiotoxicity with anthracycline-based chemotherapy mandates careful consideration of its use in older women in the adjuvant setting. Table 33.10 lists the standard adjuvant chemotherapy regimens for breast cancer.

The benefits of chemotherapy must also be weighed against the risks. The acute toxicities of standard chemotherapy regimens have been well studied, although largely in younger patient populations. These toxicities are generally short term in nature. Some degree of nausea with or without vomiting is common but usually controllable with modern antiemetics. Mild mucositis is occasionally seen, although it is almost never severe. Myelosuppression is nearly universal; however, a systemic infection occurs in less than 5% of patients. Total alopecia will occur in almost all patients who receive an anthracycline-based regimen (including doxorubicin or epirubicin), compared to approximately 50% of patients who receive CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). Weight gain is also not uncommon among women who receive adjuvant chemotherapy. Addition of paclitaxel to adjuvant chemotherapy results in an incidence of severe neuropathy of less than 5%. An increased risk of thromboembolic disease has been observed in patients receiving chemotherapy, particularly when it is given concurrently with tamoxifen. Long-term risks include a risk of less than 1% of cardiotoxicity resulting in congestive heart failure with anthracycline-based therapy, as well as a very small risk of treatment-related leukemia. It is unclear whether these risks are increased further among older women, although the risk of cardiotoxicity is increased in patients with cardiac disease, which is more common in older women.

The addition of the new biologic therapy, trastuzumab (Herceptin), to adjuvant regimens is currently being studied. Trastuzumab is a humanized monoclonal antibody to the Her-2/neu receptor, which is overexpressed in about one-third of breast cancers. The use of trastuzumab alone and in combination with chemotherapy has resulted in significant disease responses and improvements in overall survival among women with Her-2/neu-overexpressing metastatic disease. There is no reason to believe that trastuzumab would not benefit women of all age groups with Her-2/neu-positive tumors, and the treatment is generally well tolerated, although there may be an increased risk of cardiac problems in elderly. However, older women have Her-2/neu-positive tumors much less frequently than younger women.

It is widely assumed that older patients are less tolerant of chemotherapy than younger patients. Although a few small studies have reported significantly increased toxicity in the elderly, larger recent studies provide evidence to the contrary. Crivellari et al. studied the burdens and benefits of adjuvant CMF and tamoxifen in elderly women. In this group, the 76 women aged 65 years or older had higher grades of toxicity, including hematologic and mucosal toxicity, than younger women. The subjective burdens of treatment, however, were similar for older and younger patients based on quality of life measures. Begg and Carbone examined 19 Eastern Cooperative Oncology Group studies that included a total of 780 patients aged 70 years or older. These patients were compared with patients under age 70. Older patients had increased hematologic toxicity; otherwise, the incidence of severe toxicities was similar between groups. Giovanazzi-Bannon and colleagues examined data from the Illinois Cancer Center database on the 672 patients treated in phase II trials, including 271 patients aged 65 or older. Except for experiencing slightly more hematologic toxicity, there were no differences in incidence of other toxicities, dose reductions, or length of treatment delays between the two groups.

In a more recent study, Dees and colleagues treated 44 women ages 35 to 79 with early-stage breast cancer with four cycles of adjuvant AC (adriamycin and cyclophosphamide) chemotherapy. In this cohort, although myelosuppression was increased in older women, neither neutropenic complications, nor alteration in cardiac function, nor change in quality of life scores were significantly age-related. Pharmacokinetic analyses did not demonstrate age-related differences in the clearance of doxorubicin or cyclophosphamide. Although patients in these studies may represent a highly selected group, it is reassuring that the older patients appear to tolerate chemotherapy nearly as well as the younger patients.

RELATED STORIES:
Metastatic Breast Cancer   Tamoxifen   Patterns of Care   Conclusion   Prevention of Breast Cancer   Alternative Management Strategies for Local Disease   Genetics and Risk   Risk Factors   Biology and Natural History of Breast Cancer in the Elderly   Quality of Life in Older Women with Breast Cancer   Axillary Lymph Node Assessment   Ductal Carcinoma In Situ (Intraductal Carcinoma)   Epidemiology   Radiation Therapy Following Breast - Conserving Surgery   Treatment   Adjuvant Systemic Therapy   Invasive Breast Cancer: Early-Stage Disease   Summary

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