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Management of early breast cancer in the elderly

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R e v i e w o n c o l o g y Management of early breast cancer in the elderly Author Key words H. Wildiers, C. Bernard Breast cancer, elderly, surgery, radiotherapy, hormone therapy, chemotherapy, adjuvant
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R e v i e w o n c o l o g y Management of early breast cancer in the elderly Author Key words H. Wildiers, C. Bernard Breast cancer, elderly, surgery, radiotherapy, hormone therapy, chemotherapy, adjuvant Summary Breast cancer is the most frequent type of cancer in women, both in terms of incidence and mortality. Although the treatment of elderly breast cancer patients should not differ in principle from the treatment of younger patients, several specific aspects need to be considered when treating older patients. The international society of geriatric oncology (SIOG) has recently published recommendations on the management of breast cancer in the elderly. This review summarizes the most important aspects and recommendations in early breast cancer. (BJMO 2008;vol 2;5:264-9) Introduction Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in women worldwide. Nearly a third of the global number of breast cancer cases occurs in patients above age 65. In developed countries this percentage is even as high as 40%. 1 Advanced age at the diagnosis of breast cancer is associated with more favourable tumor biology as indicated by increased hormone sensitivity, attenuated HER-2/neu overexpression, and lower grades and proliferative indices. However, elderly patients present later with larger and more advanced tumors, and recent reports suggest that lymph node involvement increases with age. Elderly patients are less likely to be treated according to accepted treatment guidelines. As a consequence, undertreatment can have a strong negative impact on survival. While breast cancer occurs mainly in elderly patients, this population is significantly underrepresented in clinical trials. Collaboration with geriatricians and comprehensive geriatric assessment are of paramount importance in detecting unaddressed problems, improving functional status and possibly improving survival in elderly patients with cancer. 2 As comorbidities and functional status significantly impact on prognosis and treatment choice, great attention must be given to the overall health of elderly patients. A significant proportion of patients older than 70 years with operable breast cancer die of non-cancer-related causes. However, age alone should not be a barrier to treatment. Surgery Breast cancer surgery-related mortality is low in the elderly population, ranging from 0 to 0.3%. 4 Alternatives to conventional surgery include outpatient surgery or surgery under local anesthesia. However, this is preferably only undertaken when family support is present. Hormone therapy instead of surgery In the past, hormonal therapy has often been used as a substitute for surgery in elderly breast cancer patients because surgery was considered invasive and unlikely to affect survival, certainly in elderly women with breast cancer with limited life expectancy, such as frail patients or the very old, e.g. 80 years. 5 The impact of omitting surgery on overall survival (OS) is not clear and varies between different studies. A Cochrane meta-analysis on this topic has confirmed that primary hormonal therapy with tamoxifen is inferior to surgery (with or without hormonal therapy) for the local control and pro- 264 v o l. 2 i s s u e B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y gression-free survival of breast cancer in medically fit older women. 6 However, surgery does not result in significantly better OS and can thus be an option in frail patients with limited life expectancy who are at risk for having higher rates of local relapse which can also be very debilitating. Breast conservation therapy Breast conservation therapy (BCT) is less frequently performed in elderly breast cancer patients. 7 Since elderly patients over the age of 70 years were often excluded from trials, it is difficult to apply the conclusions of the large randomized trials of BCT versus mastectomy to the elderly population. However, smaller studies involving patients 70 years of age have documented that BCT in comparison to mastectomy is associated with better quality of life and is preferred by the majority of elderly patients when compared to mastectomy. Axillary surgery The indication for upfront axillary lymph node dissection (ALND) in elderly patients without clinical lymph node involvement is not clear, and older patients with breast cancer are less likely to undergo ALND than younger patients. Several studies failed to show any difference in outcome in older patients with small tumors without palpable lymph nodes when ALND was omitted It may be appropriate to omit ALND in elderly patients in whom the ALND results will not influence adjuvant chemotherapy decisions, including patients with small tumors and low risk of nodal involvement. In recent years however, sentinel lymph node (SLN) biopsy has been introduced as an alternative to ALND, also in patients older than 70 and is a generally accepted standard in patients of all ages with tumor size 2 to 3 cm and no clinical evidence of axillary involvement. However, in patients with clinical evidence of axillary lymph node involvement, ALND remains a standard procedure in general. Surgery should always be considered in breast cancer patients older than 70 and should not be abandoned only because of this high age. When there is clinical suspicion of axillary lymph node involvement, ALND should be used since adjuvant treatment may depend on the pathological results of the ALND. On the other hand, SLN biopsy is a safe alternative to ALND in patients with clinically node negative tumors. Elderly patients with tumor size 2 to 3 cm and no clinical evidence of axillary involvement should be offered a SLN biopsy. However, there is still controversy regarding the need for an ALND after a positive SLN. Radiotherapy Radiotherapy after breast conserving surgery Elderly patients receive radiotherapy less frequently after breast conserving surgery (BCS) than younger patients. The Early Breast Cancer Trialists Group Overview (EBCTCG), involving approximately 42,000 women with breast cancer, found that the 5-year risk of local recurrence after BCS was higher in women younger than 50 years of age (33%) compared with patients aged 70 years (13% of 3,459 in this age group). 13 The absolute effects of post-bcs radiotherapy on local recurrence (mainly in the conserved breast) were also greater for women under 50 than in older women (5-year risk reductions of 22% versus 11%, respectively) However, the risk reduction was still statistically significant in older women. A closer look to the most important large studies is interesting. The absolute incidence of relapse, as well as the absolute benefit from radiotherapy, are generally low and, with the exception of one trial, data on OS are generally absent. 14 Some studies have concluded that radiotherapy may be avoided in low-risk older patients while others have suggested it may induce slight reductions in local relapse rates and improvements in OS In patients treated with BCT and clear margins, a supplementary dose (boost) of radiation to the excision site can reduce the risk of local recurrence, also in patients over the age of 60 years. 18 Post-mastectomy radiotherapy In contrast to radiotherapy following BCS, the absolute effects of post-mastectomy radiotherapy (PMRT) on the 5-year risk of local recurrence (mainly in the chest wall or lymph nodes) have been shown to be independent of age. 13 However, few women above age 70 were included in these studies. In this meta-analysis of women who had a mastectomy, axillary clearance and node-positive disease, reductions in recurrence were about 18% in all age groups. The risk of local relapse decreases when radiotherapy after BCS is applied, and should therefore be B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y v o l. 2 i s s u e R e v i e w o n c o l o g y considered in all elderly breast cancer patients. The absolute benefit on local relapse might be small in elderly patients with low risk tumors. The influence of radiotherapy on breast cancer and non breast cancer mortality in this population is less clear and further stratification is not available. It is unlikely that radiotherapy will improve OS, which is much more influenced by comorbidity or the occurrence of distant metastases. The decision of administering radiotherapy needs to take into account patient health and functional status, risks of mortality from comorbidities (particularly cardiac and vascular) and the risks of local recurrence. Post-mastectomy chest wall radiation is indicated if patients have four or more involved nodes or a T3 or T4 tumor. Limited data are available to support the use of systematic post-mastectomy chest wall radiation therapy in patients with one to three positive nodes or node-negative with other risk factors. A boost dose of radiation to the tumor bed should be considered in older patients after BCT and systemic therapy in order to decrease risk of local relapse. Adjuvant hormonal therapy The meta-analysis from the EBCTCG demonstrated that treatment with 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% in patients with hormone receptor positive breast cancer, independent of the patients age. 19 Aromatase inhibitors are generally superior to tamoxifen in terms of DFS, but there is very little difference in OS. In terms of efficacy and side effects, no age-related differences have been documented. For hormone-sensitive breast tumors, there is a clear benefit from adjuvant hormone therapy in terms of improved relapse and survival rates. No age-related differences in the efficacy of tamoxifen and aromatase inhibitors have been reported. While aromatase inhibitors are slightly more effective than tamoxifen, elderly patients are more vulnerable to some adverse events. Therefore, safety should be an important factor when choosing between tamoxifen and aromatase inhibitors. Adjuvant chemotherapy The EBCTCG meta-analysis of randomized trials conducted before 1995 showed substantial benefits of adjuvant chemotherapy in postmenopausal women in all age groups. 19 The benefits were larger in patients younger than 50 years of age, compared to those older than 50 years of age. The benefits for patients above age 70 were in the same range as for those between 50 and 70 years of age, but were not significant due to smaller numbers. The greatest benefit of adjuvant chemotherapy in elderly patients is seen in hormone receptor-negative tumors. 20 The benefits of chemotherapy for hormone-sensitive tumors are much less obvious in the elderly. Only one phase III trial, specifically designed for elderly patients ( 65 years of age), has been published. 21 In this study, weekly flat doses of epirubicin plus tamoxifen improved DFS, compared with tamoxifen alone, but did not improve OS. Considerable uncertainty remains regarding the subgroups of older women most likely to benefit. With regards to the choice of chemotherapy, healthy older patients can basically receive the same regimens as their younger counterparts but care is warranted since elderly patients experience more toxicity. In a retrospective analysis on different CALGB studies, there was a treatment related mortality of 1.5% in elderly patients treated with different regimens (mainly anthracycline based). 22 Specific drugs/ regimens may be advisable in elderly women, and several trials are ongoing. Anthracycline-containing regimens have been shown to have superior efficacy to CMF, and this effect was not age dependent. 23 Although not specifically aimed at elderly patients, a recent study showed that docetaxel in combination with cyclophosphamide (TC) was superior compared to four cycles of AC (doxorubicin-cyclophosphamide). This effect was also seen in patients above the age of Treatment with adjuvant trastuzumab improves outcome significantly in HER-2/neu-positive patients. However, few patients aged 70 years have been included in these large trials and age above 50 was an independent predictor of trastuzumab-associated congestive heart failure. 25 Elderly patients have a higher incidence of underlying cardiac disease and as a consequence, they are probably more likely to be more sensitive to the cardiac side effects of trastuzumab than reported in the clinical trials, where underlying cardiac disease was generally one of the exclusion criteria. The decision of giving adjuvant chemotherapy should not be based on age alone, but rather take into account individual patients estimated absolute 266 v o l. 2 i s s u e B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y benefit, life expectancy, treatment tolerance and preference. Older patients with node positive, hormone negative breast tumors potentially have survival benefit. Decision aides such as Adjuvant! online (www.adjuvantonline.com) can be used to help weigh the risks and benefits of adjuvant therapy together with the patient, but it should be mentioned that this tool was not specifically validated in the elderly population ( 70 years). Four courses of an anthracycline-containing regimen are usually preferred over CMF in elderly patients with breast cancer in the absence of cardiac contraindications. In high-risk fit elderly women, taxanes could be added to anthracyclines. Docetaxel and cyclophosphamide (TC) or CMF can replace anthracyclines in patients with cardiac risk. In the absence of cardiac contraindications, adjuvant trastuzumab should be offered to older patients with HER-2 positive breast cancer when chemotherapy is indicated, but cardiac monitoring is essential. A large part of the breast cancer population is older than 70 years of age. This population is generally accepted to have an increased risk in having agerelated changes in physiology. Moreover, tumor behaviour can also be different in older versus younger breast cancer patients. This review provides evidence and consensus based recommendations on the treatment of early breast cancer in the elderly. The majority of available data rely on retrospective studies or subanalysis from general population studies. Therefore, there is a further need to develop prospective clinical trials for this older population of breast cancer patients. References 1. Wildiers H, Kunkler I, Biganzoli L, et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology. Lancet Oncol 2007;8: Extermann M, Aapro M, Bernabei R, et al. Use of comprehensive geriatric assessment in older cancer patients: Recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol 2005;55: Yancik R, Wesley M, Ries L, et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001;285: Audisio R. The surgical risk of elderly patients with cancer. Surg Oncol 2004;13: Rai S, Stotter A. Management of elderly patients with breast cancer: The time for surgery. ANZ J Surg 2005;75: Hind D, Wyld L, Beverley C, et al. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database of Systematic Reviews Giordano S, Hortobagyi G, Kau S, et al. Breast cancer treatment guidelines in older women. J Clin Oncol 2005;23: Martelli G, Miceli R, De Palo G, et al. Is axillary lymph node dissection necessary in elderly patients with breast carcinoma who have a clinically uninvolved axilla? Cancer 2003;97: Martelli G, Boracchi P, De Palo M, et al. A randomized trial comparing axillary dissection to no axillary dissection in older patients with T1N0 breast cancer - Results after 5 years of follow-up. Ann Surg 2005;242: Truong P, Bernstein V, Wai E, et al. Age-related variations in the use of axillary dissection: a survival analysis of 8038 women with T1-ST2 breast cancer. Int J Radiat Oncol Biol Phys 2002;54: Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349: Holmber S, Crivellari D, Zahrieh D, et al. A randomized trial comparing axillary clearance versus no axillary clearance in older patients (= 60 years) with breast cancer: First results of International Breast Cancer Study Group Trial J Clin Oncol 2004;22:505 (ASCO Annual Meeting Proceedings) 13. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366: Truong P, Bernstein V, Lesperance M, et al. Radiotherapy omission after breast-conserving surgery is associated with reduced breast cancer-specific survival in elderly women with breast cancer. Am J Surg 2006;191: Hughes K, Schnaper L, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351: Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: Long-term results of a randomized trial. Ann Oncol 2001;12: Smith B, Gross C, Smith G, et al. Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst 2006;98: Bartelink H, Horiot J, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345: B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y v o l. 2 i s s u e R e v i e w o n c o l o g y Key messages for clinical practice 1. Surgery - Surgery should not be denied to breast cancer patients older than 70 years of age on the basis of age alone. - Axillary lymph node dissection (ALND) should be used when there is clinical suspicion of axillary lymph node involvement. - Sentinel lymph node (SLN) biopsy is a safe alternative to ALND in patients with node negative tumors. 2. Radiotherapy - Radiotherapy after breast conserving surgery (BCS) and adjuvant systemic therapy decreases the risk of local relapse and should be considered in all elderly breast cancer patients. - The absolute benefit on local relapse might be small in elderly patients with low risk tumors, and the decision to offer radiotherapy will need to take into account patient health and functional status, risks of mortality from comorbidities (particularly cardiac and vascular), and the risks of local recurrence. - Post-mastectomy chest wall radiation is indicated if patients have four or more involved nodes or a T3 or T4 tumor and is controversial in other situations. 3. Adjuvant hormonal therapy - Elderly patients with hormone-sensitive breast tumors may benefit from adjuvant hormone therapy. - The choice between tamoxifen and aromatase inhibitors might be more influenced by the toxicity profile and comorbidities than in younger patients. 4. Adjuvant chemotherapy - The decision of giving adjuvant chemotherapy should not be based on age alone, but rather take into account individual patients estimated absolute benefit, life expectancy, treatment tolerance and preference. - Patients with node positive, hormone negative breast tumors potentially enjoy the largest benefit in survival gain, while chemotherapy in patients with hormone-sensitive low-risk tumors might cause more harm than benefit. - Anthracycline-containing regimens are usually preferred over CMF. - Docetaxel and cyclophosphamide (TC) or CMF can replace anthracyclines in patients at cardiac risk. - Adjuvant trastuzumab can be offered to older patients with HER-2 positive breast cancer when chemotherapy is indicated, but cardiac monitoring is essential. 19. Marubini E. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15- year survival: an overview of the randomised trials. Lancet 2005;365: Giordano S, Duan Z, Kuo Y, et al. 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