BREAST CANCER AND AGING

CANCER IN THE ELDERLY

0889-8588/00 $8.00

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BREAST CANCER AND AGING Clinical Interactions Gretchen G. Kimmick, MD, a n d Lodovico Balducci, MD

The most common non-skin cancer and the most common cause of cancer . ~ article discusses the death in women older than 65 years is breast ~ a n c e rThis prevalence of breast cancer in the geriatric population, the biology of breast cancer in older women, prevention of and screening for breast cancer, and problems specific to older women in the management of breast cancer. Breast cancer is primarily a disease of older women. Incidence rates of female breast cancer rise with advancing age, level off between the ages of 45 and 50 years (Clemmesen’s hook), increase again to a peak at 75 years, and decline thereafter (Fig. 1).66 Over time, the incidence of breast cancer has increased, and this increase has occurred predominantly in women over the age of 50 years. Compared with an incidence curve from 1973, a curve from 1987 shows a more dramatic increase in breast cancer incidence after age 5055(Fig. 1). With the projected increase in the geriatric population, and especially the population of women, during the next half century breast cancer will be an even greater health concern (Fig. 2). The life expectancy of women in Western societies is relatively long, about 15.5 years at the age of 70 years and 9.2 years at the age of 80 years (Table l).,O Life expectancy reflects the average number of years of remaining life for a woman in a specified population. For the individual, life expectancy depends on the presence of comorbid diseases as potential causes of mortality. Older women are at elevated risk not only for breast cancer but for multiple, concurrent

From the Department of Medicine, Section on Hematology/Oncology, Comprehensive Cancer Center of Wake Forest University, Wake Forest University School of Medicine, Winston-Salem, North Carolina (GGK); and the Senior Adult Oncology Program, H. Lee Moffitt Cancer Center and Research Institute (LB); and the Division of Medical Oncology and Hematology, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida (LB) HEMATOLOGY / ONCOLOGY CLINICS OF NORTH AMERICA

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VOLUME 14 NUMBER 1 * FEBRUARY 2000

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Figure 1. Breast cancer incidence by age. Asterisk = 1973; square = 1987. (From Kessler LG: The relationshipbetween age and incidence of breast cancer. Population and screening program data. Cancer 69:18861903, 1992; with permission.)

20,000 18,000 16,000 14,000 12,000 10,000 8,000 ~,OOO

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Figure 2. Population projections, women. Solid line = ages 65-74; dotted line = ages 75-84; dashed line = ages greater than 85.(Dafa from Statistical Abstracts of the United States, 1997. The National Data Book, 117 ed. Washington, DC, Hoover’s Business Press, 1997.)

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Table 1. AVERAGE LIFE EXPECTANCY* Age in Years

Life Expectancy of Men in Years

Life Expectancy of Women in Years

55-60 60-65 65-70 70-75 75-80 80-85 2 85

25.1 21.1 17.5 14.2 11.2 8.5 6.2

27.2 23.1 19.2 15.5 12.2 9.2 6.6

*Averagenumber of years of life remaining at the beginning of the age interval Data from Health United States 1996-7 and Injury Chartbook. Hyattsville, MD, US Department of Health and Human Services, 1997. DHHS Publication No. 97-1232; with permission

health conditions (Fig. 3). Comorbidity clearly is an important consideration for breast cancer screening and breast cancer management.81Among women with breast cancer, those over the age of 65 years have more non-breast cancer related deaths than those younger than 65 (20% versus 3%, P < 0.001)?7 This finding has been confirmed by a series of studies by Satariano et al.82-84 The risk of death increased with the number of comorbid conditions; as the number of comorbid conditions increased, the risk of breast cancer-related death also increased; and early diagnosis of breast cancer in women with multiple coexisting illnesses did 64, Io2 not improve prognosis.45,

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Figure 3. Selected chronic conditions in women, by age. In each group: First bar = arthritis; second bar = diabetes; third bar = heart disease; fourth bar = hypertension. (Data from National Center for Health Statistics: Vital and Health Statistics Series 10, No. 184. Washington, DC, US Department of Health and Human Services Public Health Services, 1992.)

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BIOLOGY OF BREAST CANCER IN OLDER WOMEN

Growth and aggressiveness of cancer are related to factors intrinsic to cancer cells and to the host’s response to the tumor. Generally, breast cancers in older women have prognostic factors indicative of less aggressiveness. The proportion of breast tumors with low proliferative indices and positive hormone receptor assays is greater in older women than in younger women.65,97 More indolent histologies, such as mucinous and papillary carcinomas, are also encountered more frequently in older age groups.102 This reduced aggressiveness was recently emphasized by the large retrospective analysis of Lyman et a1 which found that older women were more likely to have early-stage disease with a lower histologic grade, higher hormone receptor levels, and lower S-phase fractions.58In this study, good prognostic factors were associated with a better prognosis-older women experienced longer disease-free and overall survival than younger women. Breast cancers in older women are less likely to have lymphovascular invasion and mononuclear cell infiltration than tumors in younger women ( P < 0.001).70Kurtz et a1 studied the association of tumor aggressiveness and the degree of mononuclear cell infiltrati~n.~~ They found that the degree of mononuclear cell response was inversely related to the age of the patient and directly correlated with tumor growth rate. To explain the paradoxical inverse association of tumor growth and mononuclear cell infiltration, these authors postulated that mononuclear cells produced a tumor growth-stimulating cytokine. PREVENTION

Several studies have recently reported that selective estrogen receptor modulators (SERMs) may prevent breast cancer. These studies were prompted by the observation that breast cancer patients taking adjuvant tamoxifen have approximately one third fewer contralateral breast cancers than women not taking tarnoxifen6 The use of tamoxifen to decrease the incidence of breast cancer was studied and reported by three groups. The National Surgical Adjuvant Breast and Bowel Project prevention trial (NSABP P-1) was the largest of these.38It is estimated that about 17 of every 1,000 women aged 60 years will develop breast cancer over a 5-year period; women 60 years of age and older, therefore, were considered at a high enough risk that they were eligible to participate, irrespective of other risk factors. Thirty percent of the women participating were 60 years of age and older, and 6% were older than 70 years. The NSABP P-1 trial compared 5 years of tamoxifen treatment (20 mg/day orally) with a placebo. In their initial report, the NSABP summarized results in 13,175 participants followed for a mean time of 47.7 months. There was a 55% reduction in the incidence of invasive breast cancer associated with tamoxifen use in women aged 60 years or older; use of tamoxifen lowered the annual rates of invasive breast cancer from 7.33/1,000 women to 3.33/ 1,000 women. Decreases were also noted in the incidence of lesions in situ. Whereas there was a 69% decrease in estrogen receptor (ER)-positive invasive tumors, there was no apparent decrease in the rates of ER-negative invasive tumors. Unfortunately, the follow-up time was not long enough to determine an effect of tamoxifen use on overall survival, and, when the decreased incidence was found, the study was unblinded, and women receiving placebo were offered treatment with tamoxifen. This study will never indicate whether the decrease in breast cancer incidence actually translates into

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improved survival. Significant risks associated with tamoxifen in this study were a higher incidence of endometrial cancer and thromboembolic events. Two smaller randomized trials comparing tamoxifen and placebo have not confirmed the promising tamoxifen-associated prevention benefits seen in the NSABP P-1 trial. An Italian trial randomly allocated 5408 women who had had a hysterectomy to receive tamoxifen (20 mg/day orally) or placebo." At a median follow-up of 46 months, there was no overall effect on breast cancer incidence, but a subgroup analysis showed statistically significant reduction in breast cancer among women receiving tamoxifen and hormone-replacement therapy. Vascular events and hypertriglyceridemia were toxicities associated with tamoxifen use. A study from the Royal Marsden Hospital in London studied 2494 women with a family history of breast cancer randomly assigned to receive tamoxifen (20 mg/day orally) or placebo.72At a median follow-up of 70 months, the overall frequency of breast cancer was the same in both groups. It is difficult to explain fully the differences in breast cancer rates in the Italian and English reports versus the NSABP trial. In the Italian and English trials, the eligibility criteria differed from the NSABP trial, the number of older patients was much smaller, and hormone replacement therapy was allowed; these factors may account for some of the difference. Also, both of these trials excluded women older than 70 years.72,95 Overall, there is hope that tamoxifen may decrease the incidence of breast cancer, particularly in postmenopausal women. These preventive benefits may outweigh the risks for many older patients, and older women should be counseled concerning the risks and benefits of tamoxifen therapy in this setting. Preliminary evidence also suggests that tamoxifen treatment significantly decreases local recurrence and overall breast cancer events in women with ductal carcinoma in situ treated by lumpectomy and local adjuvant radiation.101 Another SERM, raloxifene, has been reported to decrease the incidence of breast cancer. Raloxifene purportedly does not have estrogen agonist effects on the uterus and may not be associated with an increased incidence of endometrial cancer." Preliminary data from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial suggest that raloxifene may be at least as good a preventive agent as tamoxifen in postmenopausal women with The second NSABP prevention trial (NSABP P-2), the Study of Raloxifene and Tamoxifen (STAR) comparing tamoxifen with raloxifene, is planned. Targeted accrual is approximately 22,000 postmenopausal women. SCREENING

The purpose of screening for breast cancer is to detect the disease at an early stage, when treatment is more effective. Breast cancer screening involves mammography, clinical breast examination, and breast self-examination. Technically, detection of cancer is easier in older women, mammographically and by physical examination, because with age the breast becomes less dense. Also, a breast abnormality in an older woman is more likely to be malignant than benign. Mammography should, theoretically, be useful in the geriatric population. Routine mammography in women aged 50 to 75 years reduces breast cancer-related mortality by 25% to 30% within 5 to 6 years of i n i t i a t i ~ n . ~ ~ Retrospective studies suggest that mammography is at least as effective in the geriatric population as in younger postmenopausal women. Comparing mammograms of women aged 50 to 64 years (n = 21,226) and those of women

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aged 65 years and older (n = 10,914), Faulk et a1 reported (1)a higher positive predictive value, (2) a higher yield of positive biopsies, and (3) a greater cancer detection rate/ 1000 studies in older w0men.3~Wilson et a1 studied prognostic characteristics of tumors detected mammographically and by other means in women aged 75 years and older.lo0Mammographically detected tumors were smaller in diameter and earlier in stage than those detected by other means. In the Nijmegen screening program, women who were screened were more likely to be diagnosed with stage I breast cancer, regardless of age.71Conversely, in a retrospective analysis by Hwang and Cody, women aged 70 years and older were less likely to have had a previous mammogram and were more likely to have axillary lymph node involvement than women aged 40 to 69 years, suggesting that the lower use of mammography led to the diagnosis of more tumors at advanced stage?' An expert panel of gerontologists and oncologists has recommended breast self-examination monthly, breast physical examination yearly, and mammography every 2 years for older women.28,29 Evidence reported by Field et a1 argues In a retrospective comparison of annual and in favor of yearly biennial screening mammography in 119 women aged 65 years and older (range 65-94 years), yearly screening mammography detected tumors that were more frequently pre-invasive (ductal carcinoma in situ [DCIS], 22% versus 7%, P = O.l), smaller (10.7 mm versus 16.5 mm, P = 0.0086), less advanced (72% versus 44% ductal carcinoma in situ or TlbNO tumors; 23% versus 37% TlcNO tumors; 2% versus 11% tumors > 2 cm with negative axillary nodes; and 3% DCIS versus 7% metastatic tumors; P = 0.0071), and less likely to involve lymph nodes (3% versus 8%, P = 0.12). Although the benefit of screening mammography may decrease with increasing age, and early diagnosis of breast cancer probably confers no survival advantage for women with a high level of comorbidity, there should probably be no rigid upper age limit for use of mammography in otherwise healthy older women.18,60, 82, ~ 4 92 , If one considers the 5 to 6 year period necessary to realize a survival benefit, then a women whose life expectancy is less than 5 years should not be screened. The remaining difficulty, however, is to predict life expectancy accurately. ISSUES SPECIFIC TO THE TREATMENT OF BREAST CANCER IN OLDER WOMEN Radiation Therapy After Lumpectomy

Treatment with local excision alone results in high local recurrence rates.4O It is well-known and well-accepted that local adjuvant radiation decreases the rate of local recurrence? In older women, however, because of the spectrum of prognostic factors discussed earlier, the need for adjuvant radiation has been questioned. Published retrospective analyses and randomized trials have addressed this question (Table 2). Reed and Morrison examined the local recurrence rates after wide local excision of clinically localized breast tumors in a group of predominantly older women and assessed the management of locoregional recurrence after ths treatm e r ~ tAxillary .~~ node dissections were not performed. No patients in the study received adjuvant systemic or radiation therapy. Of 96 women in the study with a mean age at diagnosis of 76 years, 41 patients (47%) developed recurrence, and 31 (35%) experienced locoregional recurrence at a mean of 31 months.

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Table 2. RECURRENCE FOLLOWING SURGERY ALONE AND SURGERY WITH RADIATION THERAPY IN OLDER WOMEN WITH EARLY BREAST CANCER Author

No. in Study

Reed and Morrison76 Martelli et al, 199363

96 151

Martelli et al, 199562

321

Veronesi et a194

567

Kantorowitz et

128

Type of Surgery

wide local excision, no LND lumpectomy or quadrantectomy under local anesthesia, LND only if clinical evidence of involvement lumpectomy or quadrantectomy under local anesthesia, LND only if clinical evidence of involvement quadrantectomy/ LND alone quadrantectomylLND and RT segmental mastectomy alone (77) segmental mastectomy and RT (51)

LND = lymph node dissection; RT

=

Local Recurrence Rate (YO)

35.0 4.0

5.4

8.8

0.3 39.1 4.0

radiation therapy

Isolated locoregional recurrences occurred in 15 patients (17%). The number of deaths in the patients who had recurrences were similar to the number in those that did not have recurrences. In most patients, recurrence was successfully managed with tamoxifen; few patients required radiotherapy or further surgery. Only one patient in the study developed uncontrolled local recurrence. Martelli and colleagues reported a retrospective study of 151 women aged 70 years and older with operable primary breast cancer and clinically negative axillary nodes treated with breast-sparing surgery followed by tam0xifen.6~All patients had surgery under local anesthesia. Estrogen receptors were positive for tumors in 95% of these patients. Axillary dissections were not performed if nodes were clinically negative, and adjuvant radiation therapy was not given. With a median follow-up of 5 years, there were six recurrences of breast tumors (occurring at a mean of 39 months) and six recurrences of axillary disease (occurring at a mean of 49 months), for a local failure rate of 8%. These authors reported a second analysis to re-examine the safety of this approach.62This second retrospective chart review included 321 women, of whom 298 had conservative surgery and 23 had total mastectomy. Median age at diagnosis was 77 years (range 70-92). Tumors ranged in size from less than 2 cm (Tl, 68.2%) to greater than 5 cm (T3, 0.3%); 7.5% of patients presented with tumor infiltrating the skin but not the underlying muscle. Tamoxifen was given regardless of hormone receptor status (7.9% of tumors were both ER- and progesterone receptor [PR] negative). Local failure in the breast occurred in 17 patients at a median time from initial surgery of 33 months and in the ipsilateral axilla in 13 patients at a median of 32 months. At 5 and 10 years from initial surgery, it was estimated that the local relapse rates in the breast were 5.4% and 8.7%, relapse rates in the ipsilateral axilla were 4.3% and 5.9%, and incidence of distant metastases were 6.2% and 13.4%, respectively. Of the women in the study, 25.8% died from diseases not related to breast cancer; cardiovascular disease was the most common cause of death. The local relapse rate in Martelli's report suggests that radiotherapy may be omitted in older women whose breast tumors are smaller than 2 cm.62

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Two studies addressed the need for irradiation after removal of the primary tumor in older ~ o m e n .As ~ ~expected, , ~ ~ local recurrence rates were higher in women who did not receive adjuvant radiation. Kantorowitz et a1 presented a retrospective analysis of their experience with 128 women older than 60 years treated with segmental mastectomy with (n = 51) or without (n = 77) local adjuvant radiationP3 Treatment groups were similar in clinical and histologic prognostic factors. The report did not mention tamoxifen use. Local recurrence rates were compared between women older than 60 years and younger than 59 years; in those not receiving radiation, recurrence rates were 39.1% and 22.7%, and in women who received radiation, recurrence rates were 4% and 16.7%, respectively. The relationship between age and effect of radiation was significant ( P < 0.01). With a mean follow-up of 51.4 months in women aged 60 years and older, locoregional failure occurred in 28%of patients treated with surgery alone, compared with 5% of those receiving radiation ( P < 0.005). The proportion of patients with locoregional recurrence decreased with age but was still substantial, even in patients diagnosed in their eighties: locoregional recurrence occurred in 45.5%of those aged 60 to 70 years, in 37.9%of those aged over 70 years, and 20% of those over 80 years of age. The rate of metastatic disease was unaffected by the use of radiation. The rate of radiation-induced complications was compared in women younger than 60 years and women aged 60 years and older. There was no suggestion of increased morbidity nor any instance of mortality among the older subset. Veronesi et a1 reported a randomized comparison of quadrantectomy versus quadrantectomy plus radiotherapy in postmenopausal women older than 55 years with breast cancers smaller than 2.5 cm in size.94All women in this trial also received tamoxifen. In these women treated without radiotherapy, the local relapse rate was 3.8% after a median follow-up of 39 months. The data from these two studies suggest that conservative surgery, using wide lumpectomy or quadrantectomy, in older postmenopausal patients with T1 breast cancers may provide acceptable local control. Also hoping to obviate the need for radiation therapy in older patients, several investigators studied the use of tamoxifen rather than irradiation. Results of retrospective studies, however, raise skepticism. Three of these studies reported exceedingly low local recurrence rates but included fewer than 40 pa98, lo3 In another small retrospective trial of women with node-positive tients.32,< early breast cancer, 53 patients who received tamoxifen alone following segmental mastectomy had a significantly higher frequency of breast cancer recurrence (21%) than seen in 44 patients who received tamoxifen and breast irradiation (5%).27None of the patients older than 70 years developed breast cancer recurrence. The Cancer and Leukemia Group B has implemented a prospective randomized trial (CALGB 9343) for women aged 70 years and older to resolve this issue. Schedules of irradiation given weekly may overcome the obstacle of frequent visits in the geriatric population. Rostom and colleagues reported the use of once-weekly irradiation for older patients with breast cancer who found it too difficult to receive daily treatments, usually because of distance from the treatment center?" In this study, 84 patients with a mean age of 69.2 years (range 38-91 years) with stage I to stage N breast cancer were treated with six weekly maximum doses of 6.5 Gy to the breast from two tangential fields and a similar dose was applied to the axilla and supraclavicularfossa. The calculated radiation dose used was similar to the standard total dose received after a course of 5000 to 6500 cGy delivered on a daily basis (average 175-200 cGy per fraction) over 6 to 7 weeks, a regimen thought to yield the best cosmetic result. With a follow-

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up of 3 to 7.8 years, the investigators reported local control in 59% of the 17 patients with T1 and T2 tumors. Breast fibrosis was noted in 22% of the longterm survivors. Symptomatic pneumonitis was reported in 4 patients, and brachial plexopathy was reported in 1. The weekly schedule was well-tolerated, yielded good cosmetic results with only 1 severe delayed skin reaction, and early follow-up provides encouraging results. Maher et a1 retrospectively evaluated the efficacy of combined modality therapy, including tamoxifen, 20 mg daily, and a hypofractionated course of high dose-per-fraction (HDF) onceweekly radiotherapy to a total of seven fractions, in 70 women with a mean age of 81 years (range 64-91 At a median follow-up of 36 months, the overall survival rate was 87%, the disease-specific survival rate was 88%, the disease-free survival rate was 7270, and local recurrence rate was 14%. Fortyfour percent of women in this analysis had T3 or T4 tumors at diagnosis. With the HDF regimen, 39% of patients experienced moderate fibrosis at the primary site. There were no instances of rib fractures, radiation pneumonitis, or brachial plexopathy.

Lymph Node Dissection The role of axillary lymph node dissection is coming under increasing scrutiny for women of all ages. Although it is an effective means of axillary control, the therapeutic benefits for overall disease outcome of axillary lymph node dissection in clinically node-negative patients are controversial, and its value rests primarily in the prognostic information provided.21,39 Wazer et a1 reported the 8-year outcome for 73 women aged 65 years or older with stage I or stage I1 breast cancer and clinically negative axillary lymph nodes treated with lumpectomy, breast and regional lymph node irradiation (but no axillary dissection), and t a m ~ x i f e nThey . ~ ~ reported an overall survival rate of 52.5%, a disease-free survival rate of 84%, a rate of freedom from distant metastases of 86%, a rate of cause-specific deaths of 6%, and a local failure rate of 7.5%. Radiation therapy was well-tolerated; there were no reports of arm edema, brachial plexopathy, chest wall pain, or prolonged skin breakdown; only two patients experienced transient symptomatic pneumonitis, four experienced matchline fibrosis, and three experienced persistent breast edema. Feigelson et a1 retrospectively reviewed the records of 78 women aged 70 years and older with T1 breast cancers (tumors < 2 cm in size) treated over a 10-year period at the Naval Medical Center in San Diego to determine how the results of axillary dissection influenced subsequent treatment, disease-free survival, and overall survival.35 Of the 78 women identified, 64 (82%) had axillary lymph node dissection and 14 (18%)did not. Of the 64 women who had lymph node dissection, 53 (83%) were lymph-node negative, and 11 (17%)were lymph-node positive. None of these women received adjuvant chemotherapy. The women who did not have a lymph node dissection were more likely to be treated with tamoxifen than the women whose lymph nodes were involved (P = 0.072) or known not involved ( P = 0.012). There were no statistically significant differences between the three groups with respect to disease-free survival, recurrence, or death. These authors concluded that axillary lymph node dissection is not needed to determine postoperative treatment for older patients with T1 tumors. Naslund et a1 reviewed the case notes of 332 women aged 75 years and over with primary breast cancer to determine how the information gained from axillary dissection influenced postoperative adjuvant treatment.68Only one half the patients underwent primary surgery (166 of 332); others had primary medical

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therapy (35%), delayed surgery (13%), or no therapy (2%).Axillary dissection was performed in 138 women (83%).None of the women who did not undergo axillary dissection were subjected to further surgery or radiotherapy for axillary nodal recurrence after a mean follow-up of 47 months. According to standard treatment guidelines, 59 women who received primary surgery should have had adjuvant radiation; only 21 (35%) actually received radiation. In the groups treated with primary and delayed surgery, only 54 of the 157 women (36%)with ER-positive tumors received tamoxifen. Medical Treatment of Primary Breast Cancer

Tamoxifen has been investigated as an alternative to surgery in older breast cancer patients. Despite good response rates of 30% to 60%, increasing relapse rates are found during longer follow-up, necessitating additional local treatment. Preece et a1 in Australia were the first to report the use of tamoxifen alone as initial treatment for localized breast cancer in older women." In a 4-year pilot study, 67 women aged 75 years and older (mean age 78.5 years, range 67-95 years) with clinically localized breast cancer were treated with tamoxifen, 10 to 20 mg twice daily. Forty-nine patients (73%)responded sufficiently to continue treatment; almost all the tumors that eventually responded showed signs of response after 1 month of treatment. Horobin reported 5-year results of the same series with 113 patients age 70 and older with locoregional breast cancer who, because of concurrent medical conditions, were not candidates for surgery or who had refused surgery.48Of these women, 78.8% responded for at least 6 months. Complete response (CR) occurred in 33.6%, partial response in 15%, disease was stable in 30.1%, and disease progressed in 21.2%. Time to CR ranged from 3 to 37 months, with a median of 9 months; Median duration of response for those showing a CR was 50 months. Local control of tumor was maintained in nearly one third of the patients for 5 years. Of the 89 patients who initially responded, 46 subsequently relapsed, of whom 37 went on to other treatment (18 had surgery). The actuarial 5-year survival rate was 49.4% for all patients and was highest (92%)for those showing an initial CR. Bradbeer and Kyngdon treated 161 patients older than 70 years of age with tamoxifen a10ne.l~Results were s$milar, with 61% experiencing objective regression of disease, and with CR occurring in 27%. In a Scottish trial, 100 frail older breast cancer patients (mean age of 76.4 years) were treated with tamoxifen, 10 mg three times a day, instead of surgery.'r2 At a median follow-up of 23 months, CR was seen in 39 patients, PR in 29, stable disease in 22, and progressive disease in 10.2 With longer follow-up of 59 months, 68% responded (40 CR and 28 partial response), with median response durations of 47 and 26 months, respectively.' Median time to best response was 13.5 weeks for patients achieving CR and 14 weeks for those with PR. Seventyfour percent of patients with ER-rich tumors responded. At a median follow-up of 59 months, 35% had died of breast cancer, 25% had died of other causes, and 22% remained free of recurrence; 11%underwent subsequent surgery, 32% had radiotherapy to the breast, and 40% received further hormonal therapies. Ciatto and colleagues prospectively studied 62 women aged over 69 years with operable primary breast cancer treated with tamoxifen alone to determine response ~ates.2~ Responses were documented in 29 patients (7 CR and 22 partial response) after at least 6 months of treatment. For CR, partial response, and minor response, the average times to maximal response were 24, 8.4, and 6.0 months, and the average durations of response were 10.7,17.7, and 13.0 months,

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respectively. Another 28 patients had stable disease, with an average duration of response of 16.3 months. In a later report, these authors reported that, in 120 women, response durations were limited, and progression increased over time.25 At 6, 12, 24, 36, 48, and 60 months, the proportion of subjects with responses were 43%, 57%, 56%, 46%, 32%, and 31%, respectively, and progression rates were 7%’ 12%, 25%, 39%, 55%, and 6O%, respectively; patients with stable disease accounted for the difference. They also analyzed ER content in a subset of these women and found that treatment response was strongly associated with tumor ER content. Bergman et a1 retrospectively reviewed the charts of 85 women with locoregional breast cancer aged 75 years and older in whom tamoxifen was used as primary treatment because of frailty of old age.I5The reasons for not undergoing primary surgery were physical or mental (32 patients), age (31 patients), patient’s preference (30 patients), and other (20 patients). Responses were unexpectedly low, at 37.6%, with a median time to response of 6 months for CR and 7 months for partial response. Twelve patients had a CR, all of whom remained in complete remission until death or closing date of the study. Thirty-seven patients (43.5%) developed tumor progression after tamoxifen treatment, all of whom had local progression as the first sign of progression. Of the 37 women whose disease progressed, 22 were not candidates for surgical treatment at progression because of their general condition, and 14 received salvage therapy by surgery or radiotherapy. Retrospective and prospective comparisons of tamoxifen alone compared with surgery with or without tamoxifen find tamoxifen alone to be the least effective single modality for local control of operable breast cancer, although overall survival rates are similar (Table 3). van Dalsen and de Vries retrospectively reviewed the records of women older than 70 years with breast cancer who were treated with tamoxifen alone or with ~urgery.~’ Among the 147

Table 3. TAMOXIFEN ALONE VERSUS SURGERY AND TAMOXIFEN AS INITIAL MANAGEMENT OF BREAST CANCER IN OLDER WOMEN Local Recurrence (“YO) Type of Study Author or Group

No. in Study

Retrospective Review van Dalsen and 171 de Vriesgl Tarnoxifen versus Surgery 135 Nottingham St. George Hospital,

Median Follow-up Tamoxifen Surgery Tamoxifen Surgery

41 mos

27

6

68

72

2 yrs

44

24

85

74.6

25

37.5

78.3

80.3

56

44

66

72

116 3 yrs 198841 200 6 yrs St. George Hospital, 199440 Tarnoxifen versus Surgery + Tamoxifen British Cancer 381 34 mos Research Campaign’O GRETA67 473 36 mos GRETA

=

Overall Survival (“YO)

23

7.5

82.5

84.8

25.4

6.3

82.6

79.7

Group for Research on Endocrine Therapy in the Elderly

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women who underwent surgery for nonmetastatic breast cancer, 10 (6%) had locoregional recurrence at a mean interval of 41 months. Women without metastatic disease who were treated with tamoxifen alone (n = 34) were at increased risk of locoregional recurrence or progression (27%).Mean time to local progression was 21 months. Eight of the nine patients whose tumors progressed when treated with tamoxifen alone later had surgery. In this retrospective review, the distribution of stage was uneven between the surgery group and the tamoxifen group: of patients with stage I and stage I1 diseases 84% had surgery and 56% received tamoxifen alone; of patients with stage I11 disease, 16% had surgery and 44% received tamoxifen alone. The 5-year overall survival rates of the two groups, 72% and 68%, respectively, were not affected by initial treatment. Two randomized prospective trials compared surgery with tamoxifen therapy alone and found no difference in survival rates, but locoregional control was better in surgically treated patients?",41, 78 The prospective randomized study from the St. George's Hospital of tamoxifen (20 mg/day) versus primary surgery (wide local excision for tumors < 5 cm and total mastectomy for tumors > 5 cm) in women aged 70 years and older with operable, nonmetastatic breast cancer was initiated in 1982.40,41 In the initial report, the stage distribution of tumors in the two groups was similar: approximately one tenth of the tumors were T1 and one third were T2. Local relapse was seen in 25% of women treated with tamoxifen and in 37.5% of women treated with surgery ( P = not statistically significant [NS]).41In the more recent report, the study had accrued 200 women older than 70 years4"Tumor sizes in the two groups were still similar: approximately one fifth of the tumors were T1 and one half were T2. Local progression or relapse was seen in 56% of the tamoxifen group and in 44% of the surgical group. Of the 56 patients who progressed while receiving tamoxifen, 21 had initially responded and then relapsed; the median period for regression was 2 years. There was no significant difference in time to progression in either group at a median follow-up of 6 years. Of the 100 patients treated primarily by tamoxifen, 39 had no progression, and 21 benefited from subsequent surgery; 14 patients refused surgery. The additional follow-up showed that surgery alone is more effective than treatment with tamoxifen, although, when the cross-over groups were included, the eventual results for the groups were similar. This study has been criticized, however, for including patients treated with tumorectomy, which is less than adequate surgical treatment, in the surgical group; the inclusion of these patients probably explains the unusually high relapse rate reported in the surgically treated group. In the second prospective study of tamoxifen treatment versus surgery, the Nottingham group randomly assigned women over the age of 70 years with operable breast cancer less than 5 cm in size to treatment by wedge mastectomy (n = 67) or by tamoxifen, 20 mg/twice daily (n = 68)y8Wedge mastectomy, in this study, was described as simpler than but similar in results to a simple mastectomy, and axillary dissection was performed only if the patient was symptomatic. At a mean follow-up of 25 months in the mastectomy group and 26 months in the tamoxifen group, there was no difference between the two groups in survival rate or time to systemic recurrence. Salvage mastectomy was necessary after local progression in 26 of the women initially treated with tamoxifen, and two women had inoperable tumors or were unfit for surgery at the time of progression. Two randomized trials examining the effect of surgery plus tamoxifen therapy have been reported.'", 67 The British Cancer Research Campaign conducted a trial in 381 patients aged over 70 years (median age 77 years), who were randomly assigned to receive either tamoxifen and optimal surgery (n =

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171) or tamoxifen (40 mg/day) alone (n = 183).'O Optimal surgery was defined as the surgery that the surgeon considered to be the best for the patient. At a median follow-up of 34 months, no difference in survival rate or quality of life was found. Locoregional failure occurred in 29.9% of patients receiving tamoxifen and in 13.7% of patients treated with initial surgery; further surgery was necessary in 35 patients treated with tamoxifen and in 15 patients managed with surgery and tamoxifen ( P = 0.001). The Italian Cooperative Group reported the results of a randomized, multicenter trial by the Group for Research on Endocrine Therapy in the Elderly (GRETA) comparing tamoxifen treatment alone (n = 236) with surgery plus adjuvant tamoxifen (n = 237) in 473 women aged over 70 years, Eastern Cooperative Oncology Group (ECOG) performance status 2 or lower, with operable breast cancer.67Median follow-up was 36 months. In the group treated with tamoxifen alone, 7.6% had a CR, 29.3% had a partial response, and 50.4% had stable disease. There was no operative mortality in the surgery group. Overall survival was comparable in the two treatment groups. Local disease recurrence was significantly less with surgery (6.3% versus 25.4%, P = 0.00045). In summary, only patients unfit for surgery or who decline a surgical intervention should be treated with tamoxifen alone as first-line treatment of nonmetastatic breast cancer. The use of tamoxifen alone may be reasonable for the debilitated older woman unfit to undergo surgery under general anesthesia whose tumor is not conducive to removal under local anesthesia, or for a patient whose surgery must be delayed, because of a recent myocardial infarction or stroke, for example. Tumor regression is seen in 63% of patients treated with tamoxifen alone and can persist as long as 5 years in 90% of patients who respond initially to treatment?*, Surgery, however, has advantages over tamoxifen as initial treatment, because it controls primary disease in more patients. Adjuvant Therapy

Most breast cancers in women over the age of 65 years are hormoneresponsive. Antiestrogens, or selective estrogen receptor modulators (SERMs), therefore, are very useful in treating this population. Tamoxifen is the standard antiestrogen used in this setting, because there is more than 20 years of experience with its use. The 1998 update by the Early Breast Cancer Trialists' Collaborative Group on tamoxifen treatment for early breast cancer reported that 5 years of treatment with tamoxifen is superior to 1 or 2 years of treatment; women with hormone receptor-positive breast cancers benefit greatly from adjuvant tamoxifen, regardless of age; women with hormone receptor-negative breast cancers achieve no statistically significant survival benefit from adjuvant tamoxifen; contralateral breast cancers are decreased when tamoxifen is administered; tamoxifen adds benefit when given with chemotherapy; and the benefits of tamoxifen treatment continue after discontinuation of the drug at 5 years.7In women aged 60 to 69 years and those aged 70 years and older, 5 years of adjuvant tamoxifen decreased the proportional risk of recurrence by 54% k 5% and by 54% 2 13%, respectively, and reduced the proportional risk of death by 33% 2 6% and 34% k 13%, respectively. Tamoxifen use has risks and benefits in older women that are unrelated to breast cancer.79Tamoxifen therapy protects bone and decreases osteoporotic bone fractures and may decrease cholesterol and the risk of cardiovascular events. The risks of endometrial cancers, thromboembolic events, cataracts and retinal changes, and of abnormal liver function tests are increased. Toremifene is another SERM with potential benefits in the adjuvant setting.

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Its pharmacologic profile appears similar to tamoxifen, but toremifene does not cause hepatocarcinomas in ratsz0 Adjuvant trials comparing tamoxifen and toremifene are under way.47Other SERMs with varied therapeutic profiles will undoubtedly be introduced. In the 47 adjuvant chemotherapy trials included in the 1998 meta analysis involving 18,000 women, only about 600 women (3%) were aged 70 years or 01der.~This sample size was insufficient to determine the benefits of chemotherapy in this age group. Also, the proportional reductions in recurrence and mortality decreased serially with increasing age, raising major doubts about the benefits of adjuvant chemotherapy in women over the age of 70 years. The benefits of adjuvant tamoxifen therapy remained fairly constant at approximately 30%, regardless of age (Table 4). This finding suggests that competitive causes of death do not account for the decreasing benefit of chemotherapy with increasing age; in older individuals, chemotherapy is either less effective or more toxic. For patients aged 50 to 69 years, adjuvant combination chemotherapy regimens significantly decreased the risk of recurrence; the proportional risk reductions were 20% (SD 3%) for recurrence and 11% (SD 3%) for overall mortality. This mortality reduction translates into a 2% net gain in 10-year survival for node-negative patients and a 3% net gain in 10-year survival for node-positive patients. These gains were statistically significant in women aged 50 to 69 years, but the number of older patients in the trials was too small to judge the benefits in older women, and conclusions must be made by indirect evidence. Table 5 contains the recommendations for adjuvant therapy in women over 70 years of age approved at the St. Gallen Breast Cancer Conference in 1992." These recommendations are based on results in younger postmenopausal women; clinical trials addressing the role of adjuvant chemotherapy for breast cancer in the geriatric population are needed. Extermann and colleagues used a Markov model to determine the threshold for giving adjuvant therapy to older They calculated the women, based on age, risk of recurrence, and ~ornorbidity?~ threshold risk of relapse for a gain of 1% in relapse-free and overall survival using data from the 1992 overview analysis6;it was assumed that a patient had an ER-positive tumor and had received either 5 years of tamoxifen therapy or standard chemotherapy. For women aged 80 years and older, tamoxifen therapy and chemotherapy improved only the 5-year mortality rates, irrespective of risk; 10-year mortality rates were unaffected. For women with major comorbid illness, the benefits of chemotherapy were negligible, even for women in their seventies.

Table 4. BENEFITS OF ADJUVANT THERAPIES BY AGE GROUP Proportional Risk Reductions with Tamoxifen (% f SD) Age (Years)

< 50 50-59 60-69 70 + Overall

Recurrence

45 37 54 54 47

f f f f f

8 6 5 13 13

Proportional Risk Reductions with Chemotherapy (% & SD)

Mortalitv

Recurrence

32 f 10 11 f 8 33 f 6 34 f 13 26 f 4

34 f 5' 22 f 4 18 f 4 NS 23.8 f 2.2

*Proportional risk reductions for chemotherapy are for age group 40 to 49 years. SD = standard deviation; NS = not statistically significant.

Mortalitv

27 f 5* 14 f 4 8 f 4 NS 15.2 f 2.4

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Table 5. RECOMMENDATIONS FOR ADJUVANT THERAPY FOR WOMEN MORE THAN 70 YEARS OLD Nodal Status

Adjuvant Treatment

Negative

No treatment or tamoxifen

Minimal/low risk 5 1 cm, ER andlor PR positive, and grade I Intermediate risk risk classified between low and high High risk >2 cm, or EX andlor PR negative, or grade 2-3

Tamoxifen ( + chemotherapy if ER and PR negative)

Positive ER- or PR-positive ER- and PR-negative

Tamoxifen Chemotherapy

Tamoxifen

c chemotherapy

ER = estrogen receptor; PR = progesterone receptor. Data from Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 90:1601, 1998.

Comorbid illness must be considered in all decisions regarding adjuvant therapy in older patients. Satariano and Ragland studied 936 women aged 40 to 84 years with breast cancer and identified seven comorbid conditions that are independently associated with all-cause m ~ r t a l i t y Comorbidity .~~ had a profound effect on outcome; women with three or more of the seven comorbid conditions had a 20-fold higher rate of dying from causes other than breast cancer. Desch and colleagues found that in women aged 60 to 80 years with ER-negative, node-negative breast cancer, the cost-benefit ratio of adjuvant chemotherapy was high but within the range of other commonly reimbursed procedures; for women aged 75, their model indicated that chemotherapy was associated with a 1.8-month average gain in quality-adjusted months, at a cost of $44,40O/year of life saved.31 Management of the Frail Patient with Metastatic Breast Cancer

Metastatic breast cancer is incurable. All women without life-threatening or rapidly progressive metastatic disease should, therefore, initially receive endocrine therapy, regardless of the ER and PR status of the tumor. Treatment should be focused on maintaining the highest quality of life while controlling symptoms. Tamoxifen is the recommended first-line endocrine therapy for metastatic breast cancer for women who have never received tamoxifen or who experience relapse at least 1 year after completing adjuvant tamoxifen therapy. Progression after an initial response should be managed by discontinuing tamoxifen and observing for a withdrawal response. If there is no withdrawal stabilization or response of tumor, second-line endocrine manipulation is indicated. The newer and minimally toxic aromatase inhibitors (anastrozole or letrozole) are a good choice, followed by progestins (megestrol acetate), estrogens, and corticosteroids. The use of successive endocrine agents in patients with minimally symptomatic metastases is the best approach and assures optimal quality of life for the longest period of time. Chemotherapy is generally more effective than endocrine manipulation in

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evoking tumor response, although initial treatment with endocrine therapy does not compromise survival.” 89 Responses to chemotherapy are shorter than to endocrine therapy, however, and continue an average of 6 to 12 months. The response rates to subsequent salvage chemotherapy regimens are even poorer. Older patients should be offered chemotherapy when metastases become refractory to endocrine treatment or when their symptoms require more aggressive treatment. A report on the use of chemotherapeutic agents in older patients has been recently published.” Response rates to and toxicity profiles of the standard chemotherapy regimens that are used for metastatic breast cancer are similar to those in otherwise healthy younger and older women.13, 42, 52 The severity and duration of myelosuppression is more pronounced in older patients but have not resulted in increased mortality from neutropenia, sepsis, or bleeding.=,52 Nausea and vomiting may occur less frequently in older patients,I2and psychosocial adjustment to chemotherapy appears better for older women than for younger women.69 The cardiotoxicityof anthracyclines limits the use of doxorubicin in geriatric patients especially because older patients are more susceptible to this cardiotoxi ~ i t yCardioprotectants, .~~ such as dexrazoxone, may be helpful in decreasing the 88, 93 Liposome free radicals that are believed to damage the encapsulated doxorubicin (DOXIL and others) is being tested in older patients because of its minimal cardiac toxicity and ease of admini~tration.~~ Mitoxantrone may also offer a less cardiotoxic alternative to doxorubicin, with similar efficacy.I4, The risk of anthracycline-related cardiotoxicity does not appear to be higher in otherwise healthy older women; in one series, deaths from cardiopulmonary causes were noted in 6% of women older than 65 years compared with 5% of women aged 50 to 64 Idarubicin is also an active agent in metastatic breast cancer, and in one study of 31 women older than 70 years, only 1 had a decrease in left ventricular ejection fraction after a cumulative idarubicin dose of 322 rng/m2.” Methotrexate excretion depends on renal function, which predictably decreases with increasing age. Before older women are given methotrexate, creatinine clearance should be estimated; 24-hour urine collection for calculation of creatinine clearance is strongly recommended for women with borderline estimated values. Gelman and colleagues modified methotrexate dosage on the basis of renal function in older women with advanced breast cancer without compromising its therapeutic effect.42 Oral prodrugs of 5-fluorouracil are now becoming available. Doxifluridine, which has not yet been approved for use, has been studied in a phase I1 trial of older women with advanced breast cancer! In combination with levoleucovorin, it was well-tolerated and yielded an objective response rate of 26%, with a median response duration of 7 months. Capecitabine (Xeloda) has been approved for use in metastatic breast cancer. Capecitabine is well-tolerated although hand-foot syndrome is frequent and can be d~se-limiting’~; trials in older patients are warranted. Taxanes have shown substantial activity even in heavily pretreated patients, and data concerning the use of these new agents in older patients are needed.49,75 The pharmacokinetics of vinorelbine are similar in older and younger women, and the toxicity profile is favorable.87 Trastuzumab (Herceptin), a humanized monoclonal antibody, has recently been approved for use in patients with metastatic breast cancer whose tumors This compound has few toxicities and should express HER-2 / neu (~-erbB-2).2~ be considered for use in older women with metastatic breast cancer. Reports of

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cardiotoxicity similar to that seen with anthracyclines are worrisome; cardiac function should be carefully monitored when trastuzumab is used. One of the most common sites of metastatic breast cancer is bone. Bone metastases can cause pain and be complicated by pathologic fractures. Palliation of pain has been demonstrated with strontium-89, samarium-153 lexidronam, and pamidronate.l6P 85, 86

SUMMARY

The incidence and mortality rates of breast cancer increase with age. As the geriatric population grows, the number of breast cancer cases will reach epidemic proportions. The number of coexisting medical conditions also increases with advancing age. The presence and severity of comorbid conditions influences an individual’s ability to tolerate procedures and treatments and must be considered in making disease-management decisions. Screening mammography can potentially save lives in older women. Women whose life expectancy exceeds 5 years should continue annual screening mammography. Choices for local definitive therapy, systemic adjuvant therapy, and treatment of metastatic disease should be based on patient preference and ability to tolerate the planned procedure. In general, otherwise healthy older women should be offered the same treatment options given to younger, postmenopausal women. Alternative, less aggressive, or nonstandard approaches are warranted in women whose life expectancy is limited or who are unable or unwilling to undergo standard management procedures.

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