Systemic Therapy for Older Women With Breast Cancer
Systemic Therapy for Older Women With Breast Cancer
Cancer and aging seem to go hand in hand. Most cancers and most cancer deaths occur in individuals over age 65 years. Likewise, as we age, osteoarthritis, heart disease, diabetes, and memory lapses seem to become part of our daily burden. Drs. Kimmick and Muss have detailed a strategy for managing breast cancer in older women. However, as they point out, there are several problems with defining optimal therapy for the elderly.
First, how does one define elderly? Second, there are few data from controlled clinical trials on optimal management of breast cancer in the elderly. The third issue, comorbidity, is a concern at any age. How does one separate issues of age and comorbidity on outcomes? A detailed discussion of each of these issues follows.
Identifying the Elderly
At what age do we become elderly? Is the cutoff 55, 60, 65, 70, or even 85 years of age? The literature assesses all these ages as elderly. About 40% of all breast cancers occur in the population over age 65 years. Age is a quantitative, convenient, easily applied variable. Cancer incidence, mortality, and comorbidity can all be related to age. There is no question that the incidence of breast cancer increases with age.
Many articles point out that women over age 65 are less likely to be referred to cancer centers or larger hospitals for treatment.[1,2] The treatment may be inadequate, and death may be due to other causes. As a result, the outcome for these patients appears to be less favorable. However, looking at time to progression or mortality of breast cancer patients over age 65 without correcting for stage or treatment is like comparing apples to oranges. Older persons are less likely to be referred to oncologists or to receive optimal care.[4-6] When corrections are made for stage and treatment, the outcomes for those over age 70 years are no different from those for younger patients.
Elderly Generally Excluded From Trials
Second, it is important to find clinical data to help analyze the problem of treating elderly women with breast cancer. Those over age 70 are underrepresented in cooperative group clinical trials of phase I, II, and III protocols. Although they represent a significant number of patients, women over age 70 are likely to be ineligible for clinical trials or not included for other reasons.
Some of this relates to the easy choice of tamoxifen (Nolvadex) for the estrogen receptor (ER)-positive patient, despite the involvement of multiple lymph nodes or the large size of the tumor. For younger patients with the same characteristics, treatment with chemotherapy is the first choice. In studies where chemotherapy was given to elderly patients, the combination of tamoxifen and chemotherapy was more beneficial than tamoxifen alone. In our analyses of Eastern Cooperative Oncology Group (ECOG) trials of the toxicities of chemotherapy drugs in the elderly (³ 70 years), we were not able to look at chemotherapy in breast cancer. At the time, women over age 70 were not eligible for our breast cancer chemotherapy adjuvant trials because CMF (cyclophosphamide [Cytoxan, Neosar], methotrexate, fluorouracil) was considered too toxic for those over 65.
In 1983, Begg examined the toxicity of chemotherapy in 19 trials in eight different diseases (not including breast cancer) and found little evidence of excess toxicity in subjects over age 70 enrolled in the ECOG trials, except when methotrexate was part of the protocol. In retrospect, the problem with the use of methotrexate was that it is excreted unchanged by the kidney, and renal clearance decreases in the elderly. When the dose of methotrexate was modified based on renal clearance, its effectiveness and toxicity were appropriate. A more recent study of chemotherapy in women over age 70 showed benefit comparable to that seen in younger patients.
Comorbidity and Chemotherapy
What are the issues regarding comorbidity and chemotherapy? The data show that chemotherapy in general is not more toxic in the well elderly. These data have been criticized as not being collected from a representative population of the elderly.
It is true that patients entered into studies by ECOG and others have to meet certain physiologic parameters and performance status measurements before beginning trial protocols. However, since those over 70 and those under 70 were treated with the same dose and protocols, the age factor was isolated as the variable. Having a single protocol for all elderly patients without having some physiologic parameters is not rational. The decision to treat the frail patient, elderly or not, has to be an individual decision. Not all comorbidities are contraindications to therapy.
Bergman has shown that physicians make decisions based on age rather than comorbidities. To determine the effect of age and comorbid diseases on treatment choice and survival, Bergman reviewed the medical records of 300 breast cancer patients aged 55 years and older who had been admitted to the Netherlands Cancer Institute for initial treatment between 1980 and 1987. Patients were classified according to the severity of their comorbid diseases. Physicians were found to treat women aged 75 years and older less often with adjuvant radiotherapy after a mastectomy, and more often with only primary endocrine treatment for local-stage disease.
According to the treatment guidelines of the Institute, the study sample was divided into patients who received standard vs nonstandard treatment. The treatment of 38 women (13.1%) did not correspond with the guidelines. Of these, 84% were 75 years and older and 50% had a severe comorbidity. Logistic regression analysis indicated that advanced age, per se, was a better indicator of the risk of not being treated according to protocol than comorbidity status. Cox multivariate analyses demonstrated that neither the severity of the comorbidity status nor the differences in treatment between younger and older patients had a significant effect on the risk of dying from breast cancer or on the risk of developing recurrences.
Another study using data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry showed that as women get older, they are less likely to receive radiation therapy after lumpectomy. However, those who receive radiation have a survival advantage even up to age 85 years. The results did not appear to be influenced by the presence of mortal comorbid conditions. They strongly suggest the need to carefully consider patient characteristics other than age in deciding the course of treatment for early-stage breast cancer.
Course of Disease in the Elderly
Is breast cancer more or less aggressive in the elderly? We know that there are biological differences in breast cancer in the older patient. Breast cancers in the elderly are more likely to be estrogen receptor (ER)-positive and, therefore, more likely to be treated with tamoxifen. That does not mean that ER-positive tumors in the elderly are more sensitive than ER-positive tumors in younger patients. A younger woman with ER-positive tumors and lymph node involvement is treated with chemotherapy and hormonal therapy, whereas the older patient with the same features is more likely to receive tamoxifen alone.
Data from a meta-analysis show that older women benefit from chemotherapy added to tamoxifen. The treatment of any patient should not be based primarily on age but on biological factors modified by clinical assessment of the whole patient. In other words, chronologic age should not be the sole determining factor for selecting therapies. Indeed, physiologic age is more important than chronologic age.
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