In November, a National Institutes of Health consensus panel evaluated which therapies are effective in preventing the spread of microscopic deposits of cancer cells after surgical removal of an early-stage breast tumor. The panel recommended that most women receive standard adjuvant treatments after surgeryradiation with hormonal therapy and/or chemotherapy.
Those largely left out of the recommendations, however, are women over 70 years old. The reason for this omission is simple: There are very few completed randomized trials with enough women age 70 or older to evaluate the relative benefits and morbidity of adjuvant therapies.
The pressing need for these data was advanced by Hyman B. Muss, M.D., associate director of the Vermont Cancer Center and one of the speakers at the consensus conference. Not only do elderly women have a higher risk of developing breast cancer than other age groups (see chart), but the U.S. population is aging. By 2025, for example, one out of every five Americans (20%) will be 65 years old or older, compared with 13% in 1990. And by 2030, the number of people over age 85 will have quadrupled compared to today.
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On the strength of these data, the consensus panel recommended tamoxifen for "women whose breast tumors contain estrogen-receptor protein, regardless of age, menopausal status, involvement of axillary lymph nodes, or tumor size." Possible exceptions they cited are women with tumors less than 10 millimeters in size who are either premenopausal or elderly with a history of blood clots in large veins.
Sir Richard Peto, professor of medical statistics and epidemiology at the University of Oxford and a member of the Early Breast Cancer Trialists Collaborative Group Secretariat, which conducted the meta-analysis, said, "For tamoxifen, there is massively significant evidence of benefit from the randomized trials of adjuvant therapy for receptor-positive women of all ages."
However, data for chemotherapy strategies for the elderly are limited. Unpublished data from the Oxford overview showed a decrease in the annual death rate for the elderly women treated with chemotherapy compared to those not treated. Although the analysis included 1,200 women over age 70 and showed a trend toward the same benefit seen in women aged 50 to 59 years, Muss said the data were not statistically significant.
To account for this limitation, the panel stated that "chemotherapy has been shown to substantially improve the long-term relapse-free and overall survival in both premenopausal and postmenopausal women up to age 70 years with node-positive and node-negative disease." (Therapies include cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]; cyclophosphamide and doxorubicin [CA]; cyclophosphamide, epirubicin, and 5-fluorouracil [CEF]; or CAF).
The same absence of data is seen for the elderly and radiation therapy. In a recent analysis published in May in Lancet of radiotherapy trials between 1961 and 1990, the authors concluded that the 20-year survival benefits with radiotherapy are "likely to be unfavourable for older women." This is because the risk of dying from causes other than breast cancer for the elderly seems to outweigh the benefits of radiotherapy. However, there were too few women over 70 (700) to draw a definite conclusion. A few more were included in this years unpublished Oxford overview, but the total is still less than 1,000 and was not enough to change the conclusions.
Muss pointed out that this situation is exacerbated because the elderly, in general, are less likely to receive radiation or chemotherapy after diagnosis. Part of the reason for this cautious treatment (some would say under-treatment) is that the elderly are more likely to have other illnesses.
But Muss and others showed in a 1992 article in JAMA that older women in good general health tolerate standard chemotherapy regimens almost as well as younger women. "If they have good renal function and good performance status they do pretty well," said Muss. "Interestingly enough, older people seem to have less nausea and vomiting, and some have better quality of life than younger patients."
Margaret Kemeny, M.D., one of the panel members, agreed. "A lot of studies have shown that older women can tolerate chemotherapy well if they have good performance status. Their performance status is more important than their age," said Kemeny, who is from State University of New York at Stony Brook, in Stony Brook, N.Y.
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Part of the reason for this disparity appears to be age bias on the part of physicians. A study conducted by Kemeny and presented at the annual meeting of the American Society of Clinical Oncology this year showed that physicians asked 51% of their patients under 65 to participate in clinical trials and only 35% of women over age 65. However, once they were asked, an equal percentage of younger and older patients agreed to participate. The data are being prepared for publication.
Muss cited several positive programs that have been put in motion to address some of these issues. A Cancer and Leukemia Group B study looking at the effect of radiation therapy on early stage breast cancer for women over 70 treated with lumpectomy and tamoxifen was closed in February 1999, and, according to the principal investigator, Kevin S. Hughes, M.D., of the Lahey Clinic in Burlington, Mass., preliminary results will be presented at the annual meeting of the American Society of Clinical Oncology in 2001.
In addition, the National Cancer Institute and the National Institute on Aging have initiated several joint studies for older patients, including program announcements involving cancer pharmacology and older patients, and elderly women and breast cancer. Grants were recently awarded to two cooperative groups to conduct research in older patients in their large-scale, multi-institutional trials.
Muss is the study chair of a CALGB grant that will evaluate the effect of chemotherapy in women over age 65 with early-stage breast cancer. They expect to begin recruiting patients in the next few months and will test standard chemotherapies (CMF or CA) against the oral drug capecitabine.
SWOG investigators also received funding to carry out three phase II studies in patients age 70 or older with metastatic breast, colorectal, or bladder cancer. The trials will look at the efficacy and toxicity of the drugs in elderly people, said Kathy S. Albain, M.D., of Loyola University Medical Center in Maywood, Ill., chair of the Committee on Women and Special Populations for SWOG. But Albain said the studies will also look at feasibilitywhether enough elderly patients can be accrued and whether it is possible in the cooperative group setting to collect self-reports in this population. "Were also going to collect blood samples with the first treatment to study the pharmacology of the drug since theres almost no data like this for the elderly," said Albain. Derek Raghavan, Ph.D., of the University of Southern California is the principal investigator of the grant.
Finally, another barrier for the elderly may be removed with President Clintons recent mandate to the Health Care Financing Administration to pay for older women in clinical trials.
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