Commentary (Misra/Kimmick): Managing Early-Stage Breast Cancer in Your Older Patients

August 1, 2006

As the aging population in the United States continues to grow, the incidence of diseases of the elderly, such as breast cancer, are increasing. Many more elderly women are expected to be diagnosed with new breast cancers, most of them in an early stage. Appropriate treatment of these women is important, as they have poorer outcomes when undertreated. In this review, we will discuss the biology and treatment of early breast cancer in elderly women. We will focus on the role of comorbidity and its effect on life expectancy, treatment decisions, current recommendations for primary treatment with surgery, radiation and neoadjuvant strategies, and adjuvant treatment including local radiation therapy and systemic treatment with endocrine therapy, chemotherapy, and newer agents. Finally we will discuss the importance of clinical trials in the elderly.

The inclusion of issues important to breast cancer and geriatrics makes this review by Witherby and Muss appropriate for the general oncologist. In practice, the oncologist has little randomized data to guide the treatment of older women with breast cancer and is faced with patients whose organ function and comorbidity level may increase the potential for toxicity from treatment.

Treating Older Patients

We are faced with a distinct shortage of prospective data regarding treatment of older breast cancer patients from clinical trials of adjuvant chemotherapy. As a group and individually, older patients are different from their younger counterparts. Age brings with it changes in physiology that lead to decline in organ function and differences in tumor biology. New technologies, such as gene expression profiles, may help predict which patients will benefit from adjuvant chemotherapy.

As a group, older women have breast cancers with less aggressive features. However, this is not universally true, and treatment should be based on the individual patient and tumor. We are quite certain this is done in practice, based on the fact that older women included in clinical trials have higher-risk tumors.

For example, in the Cancer and Leukemia Group B (CALGB) meta-analysis of patients with node-positive disease that Witherby and Muss reference, only 8% were over 65 years of age, and a higher percentage of the older patients had four or more positive lymph nodes compared to younger patients (61% vs 47%).[1] This not only indicates that clinicians chose older patients at higher risk for the trial, but also suggests that oncologists are generally reluctant to offer clinical trials, or perhaps standard adjuvant chemotherapy regimens, to their older patients.

Nevertheless, ongoing trials are comparing potentially less toxic regimens, such as capecitabine (Xeloda) and liposomal doxorubicin (Doxil), with standard adjuvant chemotherapy regimens for older women with breast cancer.

As Witherby and Muss also point out, there is controversy about whether older women should receive radiation therapy following breast-conserving surgery for small tumors, as it may not have an impact on overall survival, though the risk of local recurrence is higher, and such treatment affects quality of life. This is similar to the issues involved in the omission of axillary lymph node staging, and we recommend that these decisions be made on a case-by-case basis.

 

Aromatase Inhibitors

Because it is less toxic, adjuvant hormonal therapy is a clear choice in older women with hormone receptor-positive tumors. The role of aromatase inhibitors has emerged in the last few years and is still evolving. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, suggest that women who had estrogen receptor-positive, progesterone receptor-negative tumors-a profile more commonly seen in older patients-seemed to have a much better outcome with anastrozole (Arimidex) vs tamoxifen. Furthermore, with longer follow-up of these trials, we are beginning to see evidence of a survival benefit associated with the use of aromatase inhibitors in addition to or instead of tamoxifen in postmenopausal women.[2-4]

Certain side effects of aromatase inhibitors are an issue in older women. Older women are more likely to have bone loss, and aromatase inhibitors do not have the protective effect on the bone that tamoxifen has. Therefore, bone density should be monitored. From clinical experience, we have also noticed that arthralgias and myalgias can occur with aromatase inhibitor therapy, and this can be a significant issue for older patients with preexisting debilities and comorbidities, such as arthritis.

 

Means of Assessment

The issues of comorbidity and functional assessment in older patients are important but often complex, and adequate assessment can take time, with time at a premium in the clinical setting. The comprehensive geriatric assessment (CGA) involves a series of tests that help identify medical, functional, and psychosocial problems. It not only helps the provider understand the overall state of health of an older person, but also helps recognize those at risk for functional decline and treatment-related morbidity.

In a study of community-dwelling elders with cancer, the CGA helped detect deficits in activities of daily living (ADLs) or instrumental activities of daily living (IADLs), and cognitive problems that might not have been discovered otherwise.[5] But the CGA is often time-consuming and may not be a realistic tool for use in a daily oncology practice. Shorter versions of geriatric assessment are currently being developed and tested.

On the other hand, performance status and functional status assessments are quick and easy to conduct. The two methods used to assess performance status are the Karnofsky and Eastern Cooperative Oncology Group (ECOG) scales. These evaluations help assess activity level. Performance status has been shown to predict death in patients with cancer when scores are poor.[6] Functional status assessments look at a patient's ability to perform ADLs and IADLs. In the elderly population, dependence in ADLs and IADLs is predictive of poor survival.[7]

 

Comorbidities

The initial evaluation of an older patient should include careful assessment of cognition, comorbidities, and social support. The degree of cognitive impairment is important in formulating treatment plans, as the diagnosis of dementia in persons 65 and older limits median survival to 3 to 4 years.[8] Likewise, older breast cancer patients with three or more comorbidities are at a 20-fold higher risk of dying from comorbidities than from breast cancer.[9]

There is a lack of consensus regarding the types of illnessess that should be included in the assessment of comorbidity as well as appropriate scoring. Tools such as the Charlson comorbidity index may be useful in this determination and have been used by clinical investigators as part of research. Time-efficient assessment of comorbidity in the clinical setting is needed. Social support is also difficult to assess in the clinical setting, as there are many factors involved.

 

Clinical Trials

Including older breast cancer patients in clinical trials is of paramount importance. Outside a clinical trial, oncologists currently have to use their best judgment in treating older breast cancer patients because there are no evidence-based guidelines for this population.

We must always remember that a healthy 75-year-old woman can be expected to live, on average, an additional 12 years. It is definitely worth our time to learn more about risks and benefits of adjuvant chemotherapy for breast cancer in older women-how comorbidity, functional status, cognitive status, and other typical issues in geriatric medicine interact and affect treatment, and how to weigh the risks of adjuvant chemotherapy against the benefits.

-Debashish Misra, MD
-Gretchen G. Kimmick, MD, MS

Disclosures:

Dr. Kimmick has acted as a speaker for and been part of advisory boards for AstraZeneca.

References:

The inclusion of issues important to breast cancer and geriatrics makes this review by Witherby and Muss appropriate for the general oncologist. In practice, the oncologist has little randomized data to guide the treatment of older women with breast cancer and is faced with patients whose organ function and comorbidity level may increase the potential for toxicity from treatment.

Treating Older Patients

We are faced with a distinct shortage of prospective data regarding treatment of older breast cancer patients from clinical trials of adjuvant chemotherapy. As a group and individually, older patients are different from their younger counterparts. Age brings with it changes in physiology that lead to decline in organ function and differences in tumor biology. New technologies, such as gene expression profiles, may help predict which patients will benefit from adjuvant chemotherapy.

As a group, older women have breast cancers with less aggressive features. However, this is not universally true, and treatment should be based on the individual patient and tumor. We are quite certain this is done in practice, based on the fact that older women included in clinical trials have higher-risk tumors.

For example, in the Cancer and Leukemia Group B (CALGB) meta-analysis of patients with node-positive disease that Witherby and Muss reference, only 8% were over 65 years of age, and a higher percentage of the older patients had four or more positive lymph nodes compared to younger patients (61% vs 47%).[1] This not only indicates that clinicians chose older patients at higher risk for the trial, but also suggests that oncologists are generally reluctant to offer clinical trials, or perhaps standard adjuvant chemotherapy regimens, to their older patients.

Nevertheless, ongoing trials are comparing potentially less toxic regimens, such as capecitabine (Xeloda) and liposomal doxorubicin (Doxil), with standard adjuvant chemotherapy regimens for older women with breast cancer.

As Witherby and Muss also point out, there is controversy about whether older women should receive radiation therapy following breast-conserving surgery for small tumors, as it may not have an impact on overall survival, though the risk of local recurrence is higher, and such treatment affects quality of life. This is similar to the issues involved in the omission of axillary lymph node staging, and we recommend that these decisions be made on a case-by-case basis.

Aromatase Inhibitors

Because it is less toxic, adjuvant hormonal therapy is a clear choice in older women with hormone receptor-positive tumors. The role of aromatase inhibitors has emerged in the last few years and is still evolving. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, suggest that women who had estrogen receptor-positive, progesterone receptor-negative tumors-a profile more commonly seen in older patients-seemed to have a much better outcome with anastrozole (Arimidex) vs tamoxifen. Furthermore, with longer follow-up of these trials, we are beginning to see evidence of a survival benefit associated with the use of aromatase inhibitors in addition to or instead of tamoxifen in postmenopausal women.[2-4]

Certain side effects of aromatase inhibitors are an issue in older women. Older women are more likely to have bone loss, and aromatase inhibitors do not have the protective effect on the bone that tamoxifen has. Therefore, bone density should be monitored. From clinical experience, we have also noticed that arthralgias and myalgias can occur with aromatase inhibitor therapy, and this can be a significant issue for older patients with preexisting debilities and comorbidities, such as arthritis.

Means of Assessment

The issues of comorbidity and functional assessment in older patients are important but often complex, and adequate assessment can take time, with time at a premium in the clinical setting. The comprehensive geriatric assessment (CGA) involves a series of tests that help identify medical, functional, and psychosocial problems. It not only helps the provider understand the overall state of health of an older person, but also helps recognize those at risk for functional decline and treatment-related morbidity.

In a study of community-dwelling elders with cancer, the CGA helped detect deficits in activities of daily living (ADLs) or instrumental activities of daily living (IADLs), and cognitive problems that might not have been discovered otherwise.[5] But the CGA is often time-consuming and may not be a realistic tool for use in a daily oncology practice. Shorter versions of geriatric assessment are currently being developed and tested.

On the other hand, performance status and functional status assessments are quick and easy to conduct. The two methods used to assess performance status are the Karnofsky and Eastern Cooperative Oncology Group (ECOG) scales. These evaluations help assess activity level. Performance status has been shown to predict death in patients with cancer when scores are poor.[6] Functional status assessments look at a patient's ability to perform ADLs and IADLs. In the elderly population, dependence in ADLs and IADLs is predictive of poor survival.[7]

Comorbidities

The initial evaluation of an older patient should include careful assessment of cognition, comorbidities, and social support. The degree of cognitive impairment is important in formulating treatment plans, as the diagnosis of dementia in persons 65 and older limits median survival to 3 to 4 years.[8] Likewise, older breast cancer patients with three or more comorbidities are at a 20-fold higher risk of dying from comorbidities than from breast cancer.[9]

There is a lack of consensus regarding the types of illnessess that should be included in the assessment of comorbidity as well as appropriate scoring. Tools such as the Charlson comorbidity index may be useful in this determination and have been used by clinical investigators as part of research. Time-efficient assessment of comorbidity in the clinical setting is needed. Social support is also difficult to assess in the clinical setting, as there are many factors involved.

Clinical Trials

Including older breast cancer patients in clinical trials is of paramount importance. Outside a clinical trial, oncologists currently have to use their best judgment in treating older breast cancer patients because there are no evidence-based guidelines for this population.

We must always remember that a healthy 75-year-old woman can be expected to live, on average, an additional 12 years. It is definitely worth our time to learn more about risks and benefits of adjuvant chemotherapy for breast cancer in older women-how comorbidity, functional status, cognitive status, and other typical issues in geriatric medicine interact and affect treatment, and how to weigh the risks of adjuvant chemotherapy against the benefits.

-Debashish Misra, MD
-Gretchen G. Kimmick, MD, MS