Optimal management of breast cancer in the elderly patient: current perspectives
Identifieur interne : 004957 ( Pmc/Corpus ); précédent : 004956; suivant : 004958Optimal management of breast cancer in the elderly patient: current perspectives
Auteurs : Olivia Le Saux ; Bertrand Ripamonti ; Amandine Bruyas ; Olivier Bonin ; Gilles Freyer ; Marc Bonnefoy ; Claire FalandrySource :
- Clinical Interventions in Aging [ 1176-9092 ] ; 2015.
Abstract
Breast cancer (BC) is the most common female malignancy in the world and almost one third of cases occur after 70 years of age. Optimal management of BC in the elderly is a real challenge and requires a multidisciplinary approach, mainly because the elderly population is heterogeneous. In this review, we describe the various possibilities of treatment for localized or metastatic BC in an aging population. We provide an overview of the comprehensive geriatric assessment, surgery, radiotherapy, and adjuvant therapy for early localized BC and of chemotherapy and targeted therapies for metastatic BC. Finally, we attempt to put into perspective the necessary balance between the expected benefits and risks, especially in the adjuvant setting.
Url:
DOI: 10.2147/CIA.S50670
PubMed: 25609933
PubMed Central: 4293298
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PMC:4293298Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Optimal management of breast cancer in the elderly patient: current perspectives</title><author><name sortKey="Le Saux, Olivia" sort="Le Saux, Olivia" uniqKey="Le Saux O" first="Olivia" last="Le Saux">Olivia Le Saux</name><affiliation><nlm:aff id="af1-cia-10-157">Medical Oncology Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation></author><author><name sortKey="Ripamonti, Bertrand" sort="Ripamonti, Bertrand" uniqKey="Ripamonti B" first="Bertrand" last="Ripamonti">Bertrand Ripamonti</name><affiliation><nlm:aff id="af2-cia-10-157">Gynaecology-Obstetrics Department, University Hospital, Saint-Etienne, France</nlm:aff></affiliation></author><author><name sortKey="Bruyas, Amandine" sort="Bruyas, Amandine" uniqKey="Bruyas A" first="Amandine" last="Bruyas">Amandine Bruyas</name><affiliation><nlm:aff id="af3-cia-10-157">Croix Rousse University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Bonin, Olivier" sort="Bonin, Olivier" uniqKey="Bonin O" first="Olivier" last="Bonin">Olivier Bonin</name><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Freyer, Gilles" sort="Freyer, Gilles" uniqKey="Freyer G" first="Gilles" last="Freyer">Gilles Freyer</name><affiliation><nlm:aff id="af1-cia-10-157">Medical Oncology Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Bonnefoy, Marc" sort="Bonnefoy, Marc" uniqKey="Bonnefoy M" first="Marc" last="Bonnefoy">Marc Bonnefoy</name><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation><affiliation><nlm:aff id="af5-cia-10-157">Geriatric Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation></author><author><name sortKey="Falandry, Claire" sort="Falandry, Claire" uniqKey="Falandry C" first="Claire" last="Falandry">Claire Falandry</name><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation><affiliation><nlm:aff id="af5-cia-10-157">Geriatric Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25609933</idno><idno type="pmc">4293298</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293298</idno><idno type="RBID">PMC:4293298</idno><idno type="doi">10.2147/CIA.S50670</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">004957</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004957</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Optimal management of breast cancer in the elderly patient: current perspectives</title><author><name sortKey="Le Saux, Olivia" sort="Le Saux, Olivia" uniqKey="Le Saux O" first="Olivia" last="Le Saux">Olivia Le Saux</name><affiliation><nlm:aff id="af1-cia-10-157">Medical Oncology Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation></author><author><name sortKey="Ripamonti, Bertrand" sort="Ripamonti, Bertrand" uniqKey="Ripamonti B" first="Bertrand" last="Ripamonti">Bertrand Ripamonti</name><affiliation><nlm:aff id="af2-cia-10-157">Gynaecology-Obstetrics Department, University Hospital, Saint-Etienne, France</nlm:aff></affiliation></author><author><name sortKey="Bruyas, Amandine" sort="Bruyas, Amandine" uniqKey="Bruyas A" first="Amandine" last="Bruyas">Amandine Bruyas</name><affiliation><nlm:aff id="af3-cia-10-157">Croix Rousse University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Bonin, Olivier" sort="Bonin, Olivier" uniqKey="Bonin O" first="Olivier" last="Bonin">Olivier Bonin</name><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Freyer, Gilles" sort="Freyer, Gilles" uniqKey="Freyer G" first="Gilles" last="Freyer">Gilles Freyer</name><affiliation><nlm:aff id="af1-cia-10-157">Medical Oncology Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Bonnefoy, Marc" sort="Bonnefoy, Marc" uniqKey="Bonnefoy M" first="Marc" last="Bonnefoy">Marc Bonnefoy</name><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation><affiliation><nlm:aff id="af5-cia-10-157">Geriatric Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation></author><author><name sortKey="Falandry, Claire" sort="Falandry, Claire" uniqKey="Falandry C" first="Claire" last="Falandry">Claire Falandry</name><affiliation><nlm:aff id="af4-cia-10-157">Lyon University, Lyon, France</nlm:aff></affiliation><affiliation><nlm:aff id="af5-cia-10-157">Geriatric Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</nlm:aff></affiliation></author></analytic><series><title level="j">Clinical Interventions in Aging</title><idno type="ISSN">1176-9092</idno><idno type="eISSN">1178-1998</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Breast cancer (BC) is the most common female malignancy in the world and almost one third of cases occur after 70 years of age. Optimal management of BC in the elderly is a real challenge and requires a multidisciplinary approach, mainly because the elderly population is heterogeneous. In this review, we describe the various possibilities of treatment for localized or metastatic BC in an aging population. We provide an overview of the comprehensive geriatric assessment, surgery, radiotherapy, and adjuvant therapy for early localized BC and of chemotherapy and targeted therapies for metastatic BC. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Interv Aging</journal-id><journal-id journal-id-type="iso-abbrev">Clin Interv Aging</journal-id><journal-id journal-id-type="publisher-id">Clinical Interventions in Aging</journal-id><journal-title-group><journal-title>Clinical Interventions in Aging</journal-title></journal-title-group><issn pub-type="ppub">1176-9092</issn><issn pub-type="epub">1178-1998</issn><publisher><publisher-name>Dove Medical Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25609933</article-id><article-id pub-id-type="pmc">4293298</article-id><article-id pub-id-type="doi">10.2147/CIA.S50670</article-id><article-id pub-id-type="publisher-id">cia-10-157</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Optimal management of breast cancer in the elderly patient: current perspectives</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Le Saux</surname><given-names>Olivia</given-names></name><xref ref-type="aff" rid="af1-cia-10-157">1</xref></contrib><contrib contrib-type="author"><name><surname>Ripamonti</surname><given-names>Bertrand</given-names></name><xref ref-type="aff" rid="af2-cia-10-157">2</xref></contrib><contrib contrib-type="author"><name><surname>Bruyas</surname><given-names>Amandine</given-names></name><xref ref-type="aff" rid="af3-cia-10-157">3</xref><xref ref-type="aff" rid="af4-cia-10-157">4</xref></contrib><contrib contrib-type="author"><name><surname>Bonin</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="af4-cia-10-157">4</xref></contrib><contrib contrib-type="author"><name><surname>Freyer</surname><given-names>Gilles</given-names></name><xref ref-type="aff" rid="af1-cia-10-157">1</xref><xref ref-type="aff" rid="af4-cia-10-157">4</xref></contrib><contrib contrib-type="author"><name><surname>Bonnefoy</surname><given-names>Marc</given-names></name><xref ref-type="aff" rid="af4-cia-10-157">4</xref><xref ref-type="aff" rid="af5-cia-10-157">5</xref></contrib><contrib contrib-type="author"><name><surname>Falandry</surname><given-names>Claire</given-names></name><xref ref-type="aff" rid="af4-cia-10-157">4</xref><xref ref-type="aff" rid="af5-cia-10-157">5</xref><xref ref-type="corresp" rid="c1-cia-10-157"></xref></contrib></contrib-group><aff id="af1-cia-10-157"><label>1</label>Medical Oncology Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</aff><aff id="af2-cia-10-157"><label>2</label>Gynaecology-Obstetrics Department, University Hospital, Saint-Etienne, France</aff><aff id="af3-cia-10-157"><label>3</label>Croix Rousse University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</aff><aff id="af4-cia-10-157"><label>4</label>Lyon University, Lyon, France</aff><aff id="af5-cia-10-157"><label>5</label>Geriatric Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France</aff><author-notes><corresp id="c1-cia-10-157">Correspondence: Claire Falandry, Geriatrics unit, Centre Hospitalier Lyon Sud, 69495 Pierre-Benite cedex, France, Tel +33 4 78 86 15 80, Fax +33 4 78 86 57 27, Email <email>claire.falandry@chu-lyon.fr</email></corresp></author-notes><pub-date pub-type="collection"><year>2015</year></pub-date><pub-date pub-type="epub"><day>06</day><month>1</month><year>2015</year></pub-date><volume>10</volume><fpage>157</fpage><lpage>174</lpage><permissions><copyright-statement>© 2015 Le Saux et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License</copyright-statement><copyright-year>2015</copyright-year><license><license-p>The full terms of the License are available at <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.</license-p></license></permissions><abstract><p>Breast cancer (BC) is the most common female malignancy in the world and almost one third of cases occur after 70 years of age. Optimal management of BC in the elderly is a real challenge and requires a multidisciplinary approach, mainly because the elderly population is heterogeneous. In this review, we describe the various possibilities of treatment for localized or metastatic BC in an aging population. We provide an overview of the comprehensive geriatric assessment, surgery, radiotherapy, and adjuvant therapy for early localized BC and of chemotherapy and targeted therapies for metastatic BC. Finally, we attempt to put into perspective the necessary balance between the expected benefits and risks, especially in the adjuvant setting.</p></abstract><kwd-group><title>Keywords</title><kwd>elderly</kwd><kwd>breast cancer</kwd><kwd>geriatric assessment</kwd><kwd>surgery</kwd><kwd>chemotherapy</kwd><kwd>radiotherapy</kwd></kwd-group></article-meta></front><body><sec sec-type="intro"><title>Introduction</title><p>Breast cancer (BC) now represents the most common female malignancy in both the Western world and in developing countries, and is the leading cause of cancer death among women worldwide.<xref rid="b1-cia-10-157" ref-type="bibr">1</xref> Approximately one third of BCs occur over the age of 70 years.<xref rid="b2-cia-10-157" ref-type="bibr">2</xref> Aging women over 75 years have poor survival rates.<xref rid="b3-cia-10-157" ref-type="bibr">3</xref> Unlike in younger women, survival for elderly patients with BC has not improved significantly over recent years.<xref rid="b4-cia-10-157" ref-type="bibr">4</xref></p><p>The poor prognosis in older women is largely related to their unfavorable stage distribution,<xref rid="b5-cia-10-157" ref-type="bibr">5</xref> with larger tumor size at presentation, greater lymph node involvement, and more metastatic BC. This is mostly explained by delayed diagnosis in this age group.<xref rid="b6-cia-10-157" ref-type="bibr">6</xref>,<xref rid="b7-cia-10-157" ref-type="bibr">7</xref> Indeed, older patients have tumors with more favorable biological characteristics when compared with younger postmenopausal patients, ie, a higher degree of estrogen receptor (ER) and progesterone receptor expression (81% of patients ≥70 years of age in the study by Pierga et al<xref rid="b8-cia-10-157" ref-type="bibr">8</xref>), less peritumoral vascular invasion,<xref rid="b9-cia-10-157" ref-type="bibr">9</xref> less HER2/neu expression,<xref rid="b10-cia-10-157" ref-type="bibr">10</xref> lower proliferative rates, diploidy, and normal p53.<xref rid="b11-cia-10-157" ref-type="bibr">11</xref> These factors affect treatment decisions, as they are, as for the youngest patients, predictors of the risk of relapse. Furthermore, indolent tumor types, such as lobular, mucinous, and papillary mammary carcinoma, are encountered more frequently in the elderly.<xref rid="b12-cia-10-157" ref-type="bibr">12</xref></p><p>However, some studies suggest that BC in the elderly is not more indolent. In a single-institution analysis by Sigh et al in a subgroup of elderly patients (>70 years of age) with lymph node-negative disease, BC appeared to be more aggressive, with a greater risk of developing distant metastases compared with younger patients.<xref rid="b13-cia-10-157" ref-type="bibr">13</xref> Similarly, in another single-institution analysis by Wildiers et al smaller tumors seemed to be associated with increased axillary lymph node involvement.<xref rid="b14-cia-10-157" ref-type="bibr">14</xref> The hypothesis made by the authors was that small BCs in older patients have different behavior because of decreased immune defense mechanisms related to aging.</p><p>Increasing age is independently associated with decreased compliance with guidelines, decreased likelihood of surgical procedures, less frequent use of adjuvant radiation therapy following breast-conserving surgery (BCS), increased use of primary endocrine therapy,<xref rid="b15-cia-10-157" ref-type="bibr">15</xref> and decreased use of adjuvant chemotherapy even in “fit” patients.<xref rid="b16-cia-10-157" ref-type="bibr">16</xref> As a consequence, we reviewed the clinical evidence concerning BC in the elderly to help practitioners give their patients optimal and individualized treatment.</p></sec><sec><title>Pharmacologic issues</title><p>Age can have an impact on most pharmacokinetic parameters, ie, absorption, distribution, metabolism, and excretion.<xref rid="b17-cia-10-157" ref-type="bibr">17</xref> Firstly, polypharmacy can alter absorption.<xref rid="b18-cia-10-157" ref-type="bibr">18</xref> Secondly, the volume of distribution is modified by an increase in body fat, and a decline in body water and serum albumin levels. For example, with aging, the volume of distribution of anthracyclines is reduced. Thirdly, in the aging process, drug metabolism is altered by decreased hepatic function (reduced hepatic blood flow and decreased liver mass and metabolic activity, including that of the cytochrome P450 enzyme system). Lastly, after the age of 30 years, glomerular filtration and renal blood flow rates decline in a linear fashion, so that values in octagenarians are only half to two thirds those measured in young adults.<xref rid="b19-cia-10-157" ref-type="bibr">19</xref> Consequently, careful drug prescribing is mandatory in the elderly due to the physiologic changes of aging, comorbidity (such as cardiac disease), and polypharmacy. Clinical and pharmacologic data on the pharmacokinetics of chemotherapy are available.<xref rid="b20-cia-10-157" ref-type="bibr">20</xref></p></sec><sec><title>What does the Comprehensive Geriatric Assessment add to standard oncologic evaluation?</title><p>The Comprehensive Geriatric Assessment (CGA) has been evaluated in a systematic review in the oncology setting, including BC.<xref rid="b21-cia-10-157" ref-type="bibr">21</xref>,<xref rid="b22-cia-10-157" ref-type="bibr">22</xref> Geriatric assessment both adds information to a standard oncologic assessment<xref rid="b23-cia-10-157" ref-type="bibr">23</xref> and impacts treatment decisions, modifying them in 0%–49% of cases.<xref rid="b21-cia-10-157" ref-type="bibr">21</xref>,<xref rid="b24-cia-10-157" ref-type="bibr">24</xref> Conflicting findings regarding the predictive ability of geriatric assessment for treatment toxicity/complications have been reported. Several domains, including instrumental activities of daily living, poor performance status, and numerous geriatric deficits, are consistently associated with an increased mortality risk.</p><p>In the subgroup of BC, a cancer-specific Geriatric Assessment (GA) evaluating six measures (financial resources, comorbidity, obesity, physical function limitations, general mental health, and social support) predicted BC-specific survival.<xref rid="b25-cia-10-157" ref-type="bibr">25</xref> Comorbidity, cognitive function, financial status, functional limitation, and social support were associated with poor treatment tolerance and mortality,<xref rid="b26-cia-10-157" ref-type="bibr">26</xref>,<xref rid="b27-cia-10-157" ref-type="bibr">27</xref> and geriatric intervention directly influenced oncologic treatment in four of 15 BC patients.<xref rid="b28-cia-10-157" ref-type="bibr">28</xref></p><p>However, CGA lacks standardization, and specific randomized trials focusing on the effectiveness of CGA and its impact on clinical decision-making in the oncology setting and in different tumor types such as BC are still needed.</p><p>In geriatric oncology, the Vulnerable Elders Survey (VES-13),<xref rid="b29-cia-10-157" ref-type="bibr">29</xref> the Groningen Frailty Indicator,<xref rid="b30-cia-10-157" ref-type="bibr">30</xref> the G8 instrument,<xref rid="b31-cia-10-157" ref-type="bibr">31</xref> and the abbreviated CGA<xref rid="b32-cia-10-157" ref-type="bibr">32</xref> are screening tools that help identify vulnerable patients who would benefit from a full CGA. The G8 was validated in a French multicenter prospective cohort of 1,668 patients, 53.7% of whom had BC. The sensitivity of G8 was significantly superior to the VES-13 (76.6% versus 68.7%, respectively), although its specificity was inferior (64.4% versus 74.3%). When the G8 and VES-13 were used together, sensitivity increased to 86.6% but specificity decreased to 53.2%.<xref rid="b33-cia-10-157" ref-type="bibr">33</xref>,<xref rid="b34-cia-10-157" ref-type="bibr">34</xref> Other screening tools have been evaluated, such as the abbreviated CGA.<xref rid="b32-cia-10-157" ref-type="bibr">32</xref> In the specific setting of BC, the VES-13 was compared with the Barber questionnaire and showed better predictive ability for detecting frailty risk.<xref rid="b35-cia-10-157" ref-type="bibr">35</xref></p></sec><sec><title>Early stage and locally advanced breast cancer</title><sec><title>Neoadjuvant therapy</title><p>Preoperative therapy may be offered to render surgery feasible or allow BCS. It has no impact on overall survival (OS) or disease-free survival (DFS) compared with adjuvant therapy.<xref rid="b36-cia-10-157" ref-type="bibr">36</xref></p><p>In the neoadjuvant setting, hormone therapy is more often prescribed over chemotherapy. Only two Phase II studies have compared neoadjuvant endocrine therapy with chemotherapy.<xref rid="b37-cia-10-157" ref-type="bibr">37</xref>,<xref rid="b38-cia-10-157" ref-type="bibr">38</xref> The first study<xref rid="b37-cia-10-157" ref-type="bibr">37</xref> compared anastrozole or exemestane for 3 months with doxorubicin plus paclitaxel for four cycles in older postmenopausal patients with hormone receptor-positive BC. It found no statistically significant difference between the two treatment arms for clinical response rate (64% in both arms), time to response, or pathologic complete response (3% versus 6%, respectively). However, a trend toward a superior rate of BCS was observed in patients receiving endocrine therapy (33% versus 24%, <italic>P</italic>=0.58). In the second study,<xref rid="b38-cia-10-157" ref-type="bibr">38</xref> comparing epirubicin plus cyclophosphamide for four cycles versus exemestane for 24 weeks, a greater clinical response rate with chemotherapy versus hormone therapy was found (66% versus 48%), but this did not reach statistical significance (<italic>P</italic>=0.075). In contrast, patients with a low proliferation rate (Ki67 ≤10%) had a similar response rate in both treatment arms (63% versus 58%, <italic>P</italic>=0.74). Results from a multicenter Phase III study of neoadjuvant chemotherapy (FEC100) compared with hormone therapy (letrozole) are awaited (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT00963729).<xref rid="b39-cia-10-157" ref-type="bibr">39</xref> Currently, neoadjuvant endocrine therapy is used for postmenopausal patients with HR-positive BC when the risk of chemotherapy combined with surgery is greater due to advanced age or comorbidities. Indeed, it is questionable whether chemotherapy should be prescribed for older patients when toxicity is not negligible and effectiveness is not well established, especially in HR-negative BC.<xref rid="b40-cia-10-157" ref-type="bibr">40</xref> Moreover, the toxicities attributed to chemotherapy are not justified in HR-positive/HER2-negative tumors, which have a good prognosis irrespective of pathologic complete response after neoadjuvant therapy.<xref rid="b40-cia-10-157" ref-type="bibr">40</xref></p><p>Concerning endocrine therapy, a meta-analysis<xref rid="b41-cia-10-157" ref-type="bibr">41</xref> showed that aromatase inhibitors are significantly more effective and as safe as tamoxifen, and reported a clinical objective response rate (relative risk 1.29), ultrasound objective response rate (relative risk 1.29), and BCS rate (relative risk 1.36). Anastrozole, letrozole, and exemestane can be used (<xref ref-type="table" rid="t1-cia-10-157">Table 1</xref>). Continuing letrozole in responding patients beyond 3–4 months achieves a further clinical reduction in tumor size for up to 2 years.<xref rid="b42-cia-10-157" ref-type="bibr">42</xref></p><p>Limited data exist concerning neoadjuvant chemotherapy in the geriatric setting. Chemotherapy and trastuzumab seem to be interesting in fit elderly patients with HR-negative and HER2-positive BC.<xref rid="b43-cia-10-157" ref-type="bibr">43</xref> For frail or elderly patients, sequential chemotherapy might also be appropriate in order to avoid the toxicity of combination chemotherapy. Few studies have compared sequential versus combination therapy in the neoadjuvant setting. One Phase II study compared concomitant versus sequential doxorubicin and docetaxel<xref rid="b44-cia-10-157" ref-type="bibr">44</xref> and reported similar objective clinical responses but more hematologic adverse events in the concomitant arm, with more hand–foot syndrome in the sequential arm (42%).</p></sec><sec><title>Is surgery avoidable?</title><p>Elderly BC patients are sometimes denied surgery because the risk of postoperative complications and mortality is higher in this population, especially when concomitant diseases and polypharmacy are associated or when mastectomy is chosen over BCS.<xref rid="b45-cia-10-157" ref-type="bibr">45</xref>,<xref rid="b46-cia-10-157" ref-type="bibr">46</xref></p><p>Historically, primary endocrine therapy alone with tamoxifen was prescribed as an alternative to surgery.<xref rid="b47-cia-10-157" ref-type="bibr">47</xref> Nevertheless, surgery followed by endocrine therapy was shown to do better than endocrine therapy alone in PFS and specific survival<xref rid="b48-cia-10-157" ref-type="bibr">48</xref>–<xref rid="b50-cia-10-157" ref-type="bibr">50</xref> and, for one study, in overall survival.<xref rid="b51-cia-10-157" ref-type="bibr">51</xref> Primary endocrine therapy should only be offered to women with ER-positive tumors who are unfit for or refuse surgery and have a short estimated life expectancy of less than 2–3 years, since that is the median duration of response to primary endocrine therapy with tamoxifen.<xref rid="b52-cia-10-157" ref-type="bibr">52</xref>–<xref rid="b55-cia-10-157" ref-type="bibr">55</xref></p><p>However, no randomized trial has compared surgery versus primary endocrine therapy with aromatase inhibitors, which are more efficient than tamoxifen in the elderly. The UK ESTEEM (Endocrine ± Surgical Therapy for EldErly women with Mammary cancer) trial comparing primary anastrozole with surgery plus adjuvant anastrozole in women aged 75 years or older with ER-positive tumors was closed because of poor accrual. In a prospective study evaluating neoadjuvant letrozole,<xref rid="b42-cia-10-157" ref-type="bibr">42</xref> 33 of 63 women (mean age 83 years at diagnosis) evaluated remained on letrozole alone, and at 3 years the median time to treatment failure had not been reached. In conclusion, letrozole alone may provide long-term disease control for elderly women with a short life expectancy.</p></sec><sec><title>Mastectomy or BCS</title><p>Concerning surgery, the randomized European Organisation for Research and Treatment of Cancer (EORTC) 10850 trial found no difference in terms of OS and PFS between tumorectomy and modified radical mastectomy.<xref rid="b48-cia-10-157" ref-type="bibr">48</xref> However, tumorectomy plus tamoxifen is associated with improved time to distant progression<xref rid="b48-cia-10-157" ref-type="bibr">48</xref> and less functional limitation than mastectomy alone.<xref rid="b56-cia-10-157" ref-type="bibr">56</xref> Moreover, mastectomy has a negative psychologic impact for both old and younger women.<xref rid="b57-cia-10-157" ref-type="bibr">57</xref> Minimally invasive techniques such as radiofrequency ablation are under evaluation for frail elderly patients with a short life expectancy and who are not candidates for conventional surgery.<xref rid="b58-cia-10-157" ref-type="bibr">58</xref></p></sec><sec><title>Axillary dissection</title><p>Lymph node involvement and lymph node ratio are major prognostic factors in BC, even in the elderly.<xref rid="b59-cia-10-157" ref-type="bibr">59</xref> Axillary lymph node dissection enables lymph node mapping and a decision regarding adjuvant therapy, and has an impact on disease control. However, this technique has major morbidity, including lymphedema, pain, paresthesia, limited arm abduction, and altered quality of life.<xref rid="b60-cia-10-157" ref-type="bibr">60</xref> Axillary clearance can be avoided when nodes are clinically negative<xref rid="b61-cia-10-157" ref-type="bibr">61</xref>–<xref rid="b63-cia-10-157" ref-type="bibr">63</xref> and when sentinel lymph node biopsy is negative,<xref rid="b64-cia-10-157" ref-type="bibr">64</xref> with no impact on DFS, OS, or locoregional control. Concerning micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension and a primary tumor ≤5 cm, axillary dissection can be avoided, eliminating the complications of axillary surgery and with no adverse effect on survival.<xref rid="b65-cia-10-157" ref-type="bibr">65</xref></p><p>Among patients with limited metastatic sentinel lymph node involvement (1–2 nodes) T1–T2 invasive BC treated with lumpectomy, tangential whole breast irradiation, and systemic therapy, the American College of Surgeons Oncology Group Z0011 Phase III study showed that axillary dissection does not significantly improve OS or DFS.<xref rid="b66-cia-10-157" ref-type="bibr">66</xref> This conclusion was confirmed in a randomized trial evaluating all BC patients from 30 to 65 years<xref rid="b67-cia-10-157" ref-type="bibr">67</xref> and validated by the American Society of Clinical Oncology Clinical Practice Guideline Update.<xref rid="b68-cia-10-157" ref-type="bibr">68</xref></p><p>An alternative to axillary dissection is axillary radiotherapy for patients with cT1-2N0 BC up to 5 cm and a positive sentinel lymph node biopsy. In the AMAROS (After Mapping of the Axilla: Radiotherapy Or Surgery) trial, after 5 years of follow-up, there were no significant differences between axillary dissection and axillary radiotherapy in terms of DFS (86.9% versus 82.7%, <italic>P</italic>=0.1788) or OS (93.3% versus 92.5%, <italic>P</italic>=0.3386). However, 5 years after therapy, the rate of lymphedema in the surgery group was twice as high when compared with the radiotherapy group (28% versus 14%). An issue with this technique is the incomplete axillary staging. Nevertheless, axillary radiotherapy does not significantly modify adjuvant systemic therapy.<xref rid="b69-cia-10-157" ref-type="bibr">69</xref></p></sec><sec><title>Breast reconstruction</title><p>The rate of breast reconstruction after mastectomy is lower in elderly women.<xref rid="b70-cia-10-157" ref-type="bibr">70</xref>,<xref rid="b71-cia-10-157" ref-type="bibr">71</xref> This may be due to patient preference or to the physician’s reluctance to address the topic of reconstruction in this population. Age alone should not be an exclusion criterion.<xref rid="b72-cia-10-157" ref-type="bibr">72</xref> Indeed, breast reconstruction in the elderly preserves their quality of life.<xref rid="b73-cia-10-157" ref-type="bibr">73</xref> Breast site complications associated with reconstruction occur more often in older patients but are often minor. Autologous tissue-based reconstruction may provide greater benefits than implant-based reconstruction.<xref rid="b71-cia-10-157" ref-type="bibr">71</xref></p></sec></sec><sec><title>Adjuvant therapy</title><sec><title>Radiotherapy</title><sec><title>Whole breast radiation therapy following BCS</title><p>Omission of radiotherapy after BCS is controversial. Firstly, radiotherapy after BCS results in a decreased risk of ipsilateral recurrence<xref rid="b74-cia-10-157" ref-type="bibr">74</xref>,<xref rid="b75-cia-10-157" ref-type="bibr">75</xref> and BC mortality, but not in OS.<xref rid="b76-cia-10-157" ref-type="bibr">76</xref>–<xref rid="b78-cia-10-157" ref-type="bibr">78</xref> Secondly, patients aged 70–79 years with minimal comorbidity are the most likely to benefit from radiotherapy, and older patients with substantial comorbidity are the least likely to benefit from it.<xref rid="b78-cia-10-157" ref-type="bibr">78</xref> Thirdly, the risk of local recurrence declines with age, an effect likely to be enhanced by endocrine therapy.<xref rid="b79-cia-10-157" ref-type="bibr">79</xref></p><p>In this context, PRIME 2 (Post-operative Radiotherapy In Minimum-risk Elderly – Phase II), an international, randomized, controlled Phase III trial, set out to address the question of whether whole breast radiation therapy (WBRT) could be omitted in carefully defined groups of older patients.<xref rid="b80-cia-10-157" ref-type="bibr">80</xref> This trial enrolled 1,326 patients aged 65 years or older with hormone-positive, low-grade cancer, negative axillary nodes, and free-tissue margins who were receiving hormone therapy. At 5 years, the primary endpoint, ie, ipsilateral breast tumor recurrence, was 1.3% in patients who received radiotherapy and 4.1% in those who did not. DFS was significantly different, but there was no difference in OS. In accordance with this trial, a retrospective study<xref rid="b81-cia-10-157" ref-type="bibr">81</xref> and an exploratory subgroup analysis of a randomized trial<xref rid="b82-cia-10-157" ref-type="bibr">82</xref> identified a subgroup of patients with a low risk of local recurrence (T1–T2, node-negative, grade 1 tumors ≤1 cm, HR-positive) after BCS with a clear excision margin in whom postoperative radiotherapy could be omitted.</p><p>Unlike these trials, retrospective analyses showed that the elderly had lower 5-year OS and BC-specific survival and an increased risk of subsequent mastectomy when radiotherapy was omitted.<xref rid="b83-cia-10-157" ref-type="bibr">83</xref>,<xref rid="b84-cia-10-157" ref-type="bibr">84</xref> Furthermore, breast radiotherapy is well tolerated by most older BC patients without impairment of their overall health-related quality of life.<xref rid="b85-cia-10-157" ref-type="bibr">85</xref></p><p>To conclude, radiotherapy should only be omitted in frail patients with an obviously limited life expectancy and T1N0, ER-positive BC, given that the burden of local recurrence is likely not to appear before the patient dies from another cause.<xref rid="b86-cia-10-157" ref-type="bibr">86</xref> A nomogram including age, race, tumor size, ER status, and receipt of radiotherapy was developed to predict the likelihood of long-term breast preservation after BCS.<xref rid="b87-cia-10-157" ref-type="bibr">87</xref></p></sec><sec><title>Breast boost after BCS</title><p>WBRT after BCS, with a boost to the tumor bed, should be considered in all elderly patients since it decreases the risk of local relapse. The randomized EORTC 22881-10882 trial found, after a median follow-up period of 10.8 years, that a boost dose of 16 Gy led to improved local control in all age groups, but with no difference in survival.<xref rid="b88-cia-10-157" ref-type="bibr">88</xref> A total of 5,318 patients with a median age of 54.8 (25.6–78.8) years were evaluated.</p></sec><sec><title>Postmastectomy radiotherapy</title><p>There is no randomized controlled trial evaluating postmastectomy radiotherapy in elderly patients. In a retrospective analysis, postmastectomy radiotherapy was associated with improved survival in older women with high-risk (T3/4 and/or N2/3) BC.<xref rid="b89-cia-10-157" ref-type="bibr">89</xref> The SUPREMO (Selective Use of Postoperative Radiotherapy aftEr MastectOmy) trial is ongoing, with no upper limit of age in patients at intermediate risk of locoregional recurrence, ie, 1–3 positive nodes (N1), or T2 with additional risk factors, ie, grade 3 histology and/or lymphovascular invasion.<xref rid="b90-cia-10-157" ref-type="bibr">90</xref></p></sec><sec><title>Hypofractionated radiotherapy</title><p>Underuse of radiotherapy in the elderly may be related to the cost and inconvenience of a regimen protracted over several weeks. In this regard, hypofractionated radiotherapy is an attractive validated option.<xref rid="b91-cia-10-157" ref-type="bibr">91</xref> The UK START (Standardisation of Breast Radiotherapy) trial<xref rid="b92-cia-10-157" ref-type="bibr">92</xref>,<xref rid="b93-cia-10-157" ref-type="bibr">93</xref> and a randomized Canadian study<xref rid="b94-cia-10-157" ref-type="bibr">94</xref> prospectively validated two hypofractionated regimens delivering 41.6 Gy in 13 fractions and 42.5 Gy in 16 fractions, respectively. Using these regimens, locoregional relapse at 10 years did not differ significantly between standard and accelerated radiotherapy. Toxicity (breast shrinkage, telangiectasia, and breast edema) was significantly less common in the hypofractionated WBRT group in the START trial. This technique when associated with hormonal therapy is also a good alternative to surgery in nonoperable older patients and in the event of refusal to undergo surgery.<xref rid="b95-cia-10-157" ref-type="bibr">95</xref></p></sec><sec><title>Alternative to WBRT: accelerated partial breast irradiation</title><p>Various accelerated partial breast irradiation techniques, including intraoperative or postoperative brachytherapy, targeted intraoperative radiotherapy, and electron intraoperative radiotherapy, are under investigation.</p><p>Concerning postoperative accelerated partial breast irradiation, a meta-analysis<xref rid="b96-cia-10-157" ref-type="bibr">96</xref> of three randomized trials<xref rid="b97-cia-10-157" ref-type="bibr">97</xref>–<xref rid="b99-cia-10-157" ref-type="bibr">99</xref> evaluating 1,140 patients compared whole versus partial breast irradiation and found comparable OS for both treatment modalities. However, the studies included had relatively short follow-up, and partial breast irradiation was associated with a statistically significant increase in the risk of local and axillary recurrences.</p><p>However, this technique is promising in the elderly, since a single fraction therapy delivered concomitantly with surgery may avoid the inconvenience of several weeks of daily therapy. The targeted intraoperative radiotherapy technique consists of a single dose delivered concurrently with lumpectomy. It showed noninferiority to fractionated external beam radiotherapy with regard to local recurrence in the conserved breast. Wound-related complications were much the same between the groups, but grade 3 or 4 skin complications were significantly reduced with targeted intraoperative radiotherapy.<xref rid="b100-cia-10-157" ref-type="bibr">100</xref>,<xref rid="b101-cia-10-157" ref-type="bibr">101</xref> This is an option for low-risk patients (ER-positive, no nodal involvement, no lymphovascular invasion, grade 1–2, clear excision margins). Another technique, ie, electron intraoperative radiotherapy, was evaluated in an equivalence randomized trial.<xref rid="b102-cia-10-157" ref-type="bibr">102</xref> In women with early small BC, electron intraoperative radiotherapy resulted in significantly more local recurrence than did conventional postoperative external radiotherapy after 5 years of follow-up, but OS did not differ between the groups.<xref rid="b102-cia-10-157" ref-type="bibr">102</xref></p></sec></sec><sec><title>Adjuvant systemic therapy</title><sec><title>Adjuvant endocrine therapy</title><p>Omission of endocrine therapy is an option for patients with very low-risk tumors (≤10 mm, grade 1 ductal carcinoma, grade 1 or 2 lobular carcinoma).<xref rid="b103-cia-10-157" ref-type="bibr">103</xref> In other cases, for HR-positive tumors, adjuvant endocrine therapy is indicated. Aromatase inhibitors are preferred to tamoxifen for their safety and efficacy. In a subgroup analysis of the Breast International Group (BIG) 1-98 Collaborative Group, adjuvant treatment with letrozole, compared with tamoxifen, significantly improved DFS, OS (hazard ratio 0.82), and time to distant recurrence.<xref rid="b104-cia-10-157" ref-type="bibr">104</xref>,<xref rid="b105-cia-10-157" ref-type="bibr">105</xref> Elderly healthy patients completing 5 years of tamoxifen should be considered for extended adjuvant therapy with letrozole.<xref rid="b106-cia-10-157" ref-type="bibr">106</xref></p><p>Concerning toxicity, aromatase inhibitors are associated with fewer thromboembolic events, endometrial cancers,<xref rid="b107-cia-10-157" ref-type="bibr">107</xref> and cognitive impairment<xref rid="b108-cia-10-157" ref-type="bibr">108</xref> when compared with tamoxifen. On the other hand, aromatase inhibitors are associated with more bone fractures<xref rid="b107-cia-10-157" ref-type="bibr">107</xref> and musculoskeletal adverse events. In the exploratory analysis of ATAC (Arimidex Tamoxifen Alone or in Combination), 35.2% of women treated with anastrozole developed joint symptoms.<xref rid="b109-cia-10-157" ref-type="bibr">109</xref> These symptoms are a frequent reason for discontinuing therapy (20%).<xref rid="b110-cia-10-157" ref-type="bibr">110</xref> In routine clinical practice, only 69% of women on anastrozole remained adherent to this therapy.<xref rid="b111-cia-10-157" ref-type="bibr">111</xref> In this regard, the PROACTIVE (RECF2252) trial evaluating the impact of geriatric intervention on endocrine therapy observance is ongoing.<xref rid="b112-cia-10-157" ref-type="bibr">112</xref> Furthermore, aromatase inhibitors are associated with a 1.5 times higher risk of bone fractures than tamoxifen (from 0.9% to 11%).<xref rid="b113-cia-10-157" ref-type="bibr">113</xref> All patients initiating aromatase inhibitors should be encouraged to undertake physical activity and to receive bone mineral densitometry, calcium/vitamin D supplements, and antiresorptive therapy if their T-score for bone mineral density is less than –2.0 or if they have two or more risk factors for fracture. Unsatisfactory compliance/decreasing bone mineral density after 12–24 months on oral bisphosphonates should trigger a switch to intravenous bisphosphonate therapy.<xref rid="b114-cia-10-157" ref-type="bibr">114</xref> Finally, specific adverse events predict a survival benefit in patients treated with aromatase inhibitors.<xref rid="b115-cia-10-157" ref-type="bibr">115</xref></p></sec><sec><title>Adjuvant chemotherapy</title><p>The challenge in geriatric oncology is to balance the potential benefits and risks of adjuvant therapy. The majority of BCs in women aged 70 years and older are HR-positive and HER2-negative. The major issue in these patients, most of whom are candidates for endocrine therapy, is the potential added value of chemotherapy. The decision regarding adjuvant therapy should be taken considering life expectancy<xref rid="b116-cia-10-157" ref-type="bibr">116</xref> (for example, with the 4-year mortality prognostic index developed by Lee et al),<xref rid="b116-cia-10-157" ref-type="bibr">116</xref> cancer prognosis,<xref rid="b117-cia-10-157" ref-type="bibr">117</xref> and the estimated reduction in risk of recurrence and specific mortality.<xref rid="b118-cia-10-157" ref-type="bibr">118</xref></p><p>The risk of relapse can be estimated using the Adjuvant! computer program developed by Ravdin et al<xref rid="b119-cia-10-157" ref-type="bibr">119</xref> or the 70-gene signature.<xref rid="b120-cia-10-157" ref-type="bibr">120</xref> Adjuvant! was developed to estimate 10-year DFS and OS incorporating all of the prognostic factors except for HER2 tumor status. This tool helps the clinician to estimate the outcome with local treatment only and the potential benefit of systemic therapy. It should be noted that Adjuvant! was developed using data from patients up to 69 years of age and that the effectiveness of second-generation and third-generation chemotherapy regimens in older patients, as estimated by Adjuvant!, has not been validated in clinical trials, and it is possible that the value of such regimens is overestimated in this patient group. Adjuvant! also integrates patient age into its survival calculations and can be adjusted to account for comorbidity, which is extremely helpful information when discussing the risks and benefits of treatment with older patients.</p><p>However, the benefits of adjuvant therapy in the elderly must be weighted by some elements. First, in older patients, comorbidities and competing causes of deaths<xref rid="b121-cia-10-157" ref-type="bibr">121</xref> are more frequent. Second, the gain in reduction of recurrence or mortality as a result of adjuvant therapy is less important in older patients.<xref rid="b118-cia-10-157" ref-type="bibr">118</xref>,<xref rid="b122-cia-10-157" ref-type="bibr">122</xref>,<xref rid="b123-cia-10-157" ref-type="bibr">123</xref> Third, the toxicity of adjuvant chemotherapy is higher. Indeed, adjuvant polychemotherapy has substantial toxic effects (around 60%–70% grade 3 or 4 adverse events),<xref rid="b124-cia-10-157" ref-type="bibr">124</xref> more grade 4 hematologic toxicity, more treatment discontinuation for toxicity, and more acute myeloid leukemia/myelodysplastic syndrome (1.8%).<xref rid="b125-cia-10-157" ref-type="bibr">125</xref> Age is a risk factor for the development of myelodysplasia and acute myelogenous leukemia after anthracycline-based adjuvant chemotherapy for BC.<xref rid="b126-cia-10-157" ref-type="bibr">126</xref> In a retrospective review of four randomized Cancer and Leukemia Group B (CALGB) trials,<xref rid="b124-cia-10-157" ref-type="bibr">124</xref> older patients had higher chemotherapy-related mortality (1.5% of patients aged ≥65 years), and the incidence of treatment-related mortality increased linearly with age. Recently, the phenomenon of “chemobrain” (long-term chemotherapy-induced cognitive impairment) has been described and has been associated with altered quality of life and functionality.<xref rid="b127-cia-10-157" ref-type="bibr">127</xref> Moreover, adjuvant chemotherapy was shown to have a progerontogenic effect, estimated as 10.4 years of chronologic aging.<xref rid="b128-cia-10-157" ref-type="bibr">128</xref></p><p>The other barrier to adjuvant therapy is the feasibility of chemotherapy in the elderly. Indeed, as outlined above, standard chemotherapy regimens prescribed for younger patients, such as cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), result in higher grade 3 toxicities (hematologic events, mucosal toxicity) and more dose reductions.<xref rid="b129-cia-10-157" ref-type="bibr">129</xref>,<xref rid="b130-cia-10-157" ref-type="bibr">130</xref></p><p>The subgroup of patients in whom chemotherapy is associated with a significant reduction in mortality is HR-negative BC irrespective of pN status.<xref rid="b131-cia-10-157" ref-type="bibr">131</xref>,<xref rid="b132-cia-10-157" ref-type="bibr">132</xref> Its role in HR-positive BC remains controversial. In this regard, GERICO (the French Group of Geriatric Oncology) has developed a trial to evaluate the benefit of adjuvant chemotherapy with regard to OS in patients aged over 70 years, with pN0 or pN-positive, HR-positive HER2-negative disease, and with a high genomic grade index assessed by reverse transcriptase polymerase chain reaction (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT01564056).<xref rid="b133-cia-10-157" ref-type="bibr">133</xref></p><p>Elderly patients should be given clear information regarding the benefits and risks of therapy, given the fact that the toxicity is not negligible and the benefit is sometimes modest. They should become active participants in the decision to adhere to such treatment.<xref rid="b134-cia-10-157" ref-type="bibr">134</xref></p><p>As for younger patients, polychemotherapies are more efficient than monotherapy.<xref rid="b135-cia-10-157" ref-type="bibr">135</xref> In the CALGB 49907 trial, standard adjuvant chemotherapy with CMF or doxorubicin plus cyclophosphamide was superior to capecitabine alone in fit patients over 65 years.<xref rid="b124-cia-10-157" ref-type="bibr">124</xref> Only one Phase III trial compared adjuvant epirubicin plus tamoxifen versus tamoxifen alone, but the difference in DFS did not reach statistical significance.<xref rid="b136-cia-10-157" ref-type="bibr">136</xref></p><p>Anthracyclines are another option. However, the risk of being diagnosed with congestive heart failure is increased in elderly women.<xref rid="b137-cia-10-157" ref-type="bibr">137</xref> In this regard, the International Society of Geriatric Oncology recommends the use of liposomal anthracycline formulations.<xref rid="b138-cia-10-157" ref-type="bibr">138</xref></p><p>In fit elderly women aged 70–85 years with HR-negative early BC and a significant risk of recurrence, four cycles of non-pegylated liposomal doxorubicin plus cyclophosphamide was feasible but had a certain impact on social and role functioning; however, autonomy was preserved and toxicity was acceptable.<xref rid="b139-cia-10-157" ref-type="bibr">139</xref></p><p>The other feasible regimen is four cycles of adjuvant docetaxel plus cyclophosphamide.<xref rid="b140-cia-10-157" ref-type="bibr">140</xref>,<xref rid="b141-cia-10-157" ref-type="bibr">141</xref> Docetaxel plus cyclophosphamide was compared with doxorubicin plus cyclophosphamide in one study.<xref rid="b142-cia-10-157" ref-type="bibr">142</xref> In patients aged 65–74 years, docetaxel plus cyclophosphamide was superior to standard doxorubicin plus cyclophosphamide in terms of DFS and OS. However, older women experienced higher rates of febrile neutropenia.<xref rid="b143-cia-10-157" ref-type="bibr">143</xref> The last feasible regimen in patients aged 65–77 years is 5-fluorouracil, epirubicin, and cyclophosphamide with pegfilgrastim support.<xref rid="b144-cia-10-157" ref-type="bibr">144</xref></p><p>In conclusion, the chemoregimens possible are CMF (with precautions), anthracyclines plus cyclophosphamide with a preference for liposomal anthracyclines, and docetaxel plus cyclophosphamide. Capecitabine alone is not recommended. Primary prophylaxis with granulocyte colony-stimulating factor should be discussed before initiating adjuvant chemotherapy.<xref rid="b145-cia-10-157" ref-type="bibr">145</xref></p></sec><sec><title>Adjuvant HER2-targeted therapy</title><p>Age itself should not be a contraindication, but cardiac function should be carefully monitored.<xref rid="b146-cia-10-157" ref-type="bibr">146</xref> RESPECT (N-SAS BC07; <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT01104935), a randomized controlled trial evaluating trastuzumab without chemotherapy as postoperative adjuvant therapy in women aged 70–80 years, is ongoing.<xref rid="b147-cia-10-157" ref-type="bibr">147</xref></p></sec></sec></sec><sec><title>Metastatic breast cancer</title><sec><title>Endocrine therapy</title><p>Elderly women with HR-positive metastatic BC should be treated like postmenopausal women, regardless of age. Aromatase inhibitors are superior to tamoxifen and better tolerated. In first-line, anastrozole,<xref rid="b148-cia-10-157" ref-type="bibr">148</xref>,<xref rid="b149-cia-10-157" ref-type="bibr">149</xref> letrozole,<xref rid="b150-cia-10-157" ref-type="bibr">150</xref>,<xref rid="b151-cia-10-157" ref-type="bibr">151</xref> and exemestane<xref rid="b152-cia-10-157" ref-type="bibr">152</xref> have shown their superiority. In second-line, fulvestrant and anastrozole have been shown to be similar in terms of OS.<xref rid="b153-cia-10-157" ref-type="bibr">153</xref> In the BOLERO (Breast cancer trials of OraL EveROlimus)-2 trial,<xref rid="b154-cia-10-157" ref-type="bibr">154</xref> addition of everolimus to exemestane after progression on nonsteroidal aromatase inhibitors improved PFS. Elderly everolimus-treated patients had incidences of adverse events (stomatitis, infections, rash, pneumonitis, and hyperglycemia) that were similar to those in younger patients, but had more on-treatment deaths.<xref rid="b154-cia-10-157" ref-type="bibr">154</xref></p><p>One Phase II study compared letrozole plus cyclophosphamide versus letrozole alone<xref rid="b155-cia-10-157" ref-type="bibr">155</xref> and found an overall response rate of 71.9% in 57 patients randomly assigned to receive primary letrozole and 87.7% in 57 patients randomly assigned to receive letrozole plus cyclophosphamide.</p></sec><sec><title>Chemotherapy</title><p>Chemotherapy is recommended in elderly women with HR-negative or rapidly progressing metastatic BC, with a preference for monotherapy and oral and weekly chemotherapies. The chemotherapy regimens that can be prescribed are summarized in <xref ref-type="table" rid="t2-cia-10-157">Tables 2</xref>–<xref ref-type="table" rid="t4-cia-10-157">4</xref>. Considering monotherapies (<xref ref-type="table" rid="t2-cia-10-157">Table 2</xref>), anthracyclines are important drugs in BC. However, congestive heart failure is more frequent in patients aged 65 years and over.<xref rid="b156-cia-10-157" ref-type="bibr">156</xref> In this context, pegylated liposomal doxorubicin was proposed as an interesting alternative<xref rid="b138-cia-10-157" ref-type="bibr">138</xref>,<xref rid="b157-cia-10-157" ref-type="bibr">157</xref> but appears poorly tolerated in the very old and in vulnerable patients.<xref rid="b158-cia-10-157" ref-type="bibr">158</xref>–<xref rid="b160-cia-10-157" ref-type="bibr">160</xref> Capecitabine at a reduced dose of 2,000 mg/m<sup>2</sup><xref rid="b161-cia-10-157" ref-type="bibr">161</xref>,<xref rid="b162-cia-10-157" ref-type="bibr">162</xref> and intravenous or oral vinorelbine<xref rid="b163-cia-10-157" ref-type="bibr">163</xref>,<xref rid="b164-cia-10-157" ref-type="bibr">164</xref> appear to be acceptable monochemotherapies with good benefit/risk ratios, provided follow-up is sufficient. The 1,000 mg/m<sup>2</sup> twice daily capecitabine dose is the standard since two toxic deaths occurred in the trial by Bajetta et al (in advanced BC)<xref rid="b161-cia-10-157" ref-type="bibr">161</xref> and another two toxic deaths in the CALGB 49907 trial (adjuvant chemotherapy)<xref rid="b124-cia-10-157" ref-type="bibr">124</xref> at the dose of 1,250 mg/m<sup>2</sup> twice daily. Several studies have shown the efficacy and safety of paclitaxel<xref rid="b165-cia-10-157" ref-type="bibr">165</xref>–<xref rid="b167-cia-10-157" ref-type="bibr">167</xref> and docetaxel<xref rid="b168-cia-10-157" ref-type="bibr">168</xref>–<xref rid="b170-cia-10-157" ref-type="bibr">170</xref> in elderly patients. Cardiovascular complications must be monitored with paclitaxel,<xref rid="b165-cia-10-157" ref-type="bibr">165</xref> and docetaxel was proposed to be initiated at 26 mg/m<sup>2</sup> with dose escalation in the event of no toxicity.<xref rid="b170-cia-10-157" ref-type="bibr">170</xref> Finally, eribulin appears to be a good alternative in heavily pretreated metastatic BC, without any major impact of age on treatment tolerance.<xref rid="b171-cia-10-157" ref-type="bibr">171</xref></p><p>Considering polychemotherapies (<xref ref-type="table" rid="t4-cia-10-157">Table 4</xref>), a combination of gemcitabine and vinorelbine in elderly patients with anthracycline-pretreated and taxane-pretreated metastatic BC showed activity and safety (response rate 33.3%, PFS 6.2 months, OS 17.0 months).<xref rid="b172-cia-10-157" ref-type="bibr">172</xref> A multicenter pilot study by GERICO assessed the effect of an oral combination of capecitabine and vinorelbine in patients with advanced breast, prostate, or lung cancer.<xref rid="b173-cia-10-157" ref-type="bibr">173</xref> After three cycles, 42.9% had stabilized disease. Compliance was excellent (68.8%). The most common grade 3–4 toxicities were hematologic (17.9%) and gastrointestinal (7.7%).</p><p>The treatment of cancer patients near death is becoming increasingly aggressive over time,<xref rid="b174-cia-10-157" ref-type="bibr">174</xref> whereas the benefit decreases with the line of chemotherapy.<xref rid="b175-cia-10-157" ref-type="bibr">175</xref> Consequently, the decision to begin another line of chemotherapy should be taken with the patient after information regarding the potential benefits and risks.</p></sec><sec><title>HER2-targeted therapy</title><p>The prevalence of HER2-overexpressing tumors in elderly women ranges between 7% and 20%. The major concern about trastuzumab is its safety, given its nearly doubled risk of cardiac events,<xref rid="b176-cia-10-157" ref-type="bibr">176</xref> especially in patients with cardiovascular risk factors, such as a history of cardiac disease and diabetes.<xref rid="b177-cia-10-157" ref-type="bibr">177</xref> Trastuzumab can be given to fit patients with continuous cardiac monitoring and acceptable tolerance.<xref rid="b178-cia-10-157" ref-type="bibr">178</xref>,<xref rid="b179-cia-10-157" ref-type="bibr">179</xref></p><p>A multicenter, retrospective, observational Italian study reported that use of trastuzumab with taxanes or vinorelbine was associated with a 67% response rate and a median time to progression of 8.7 months.<xref rid="b180-cia-10-157" ref-type="bibr">180</xref> Subgroup analyses from the randomized, double-blind, placebo-controlled Phase III CLEOPATRA trial (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT00567190) in older patients (median age 69 years) showed improved PFS with pertuzumab plus trastuzumab plus docetaxel. This chemotherapy regimen was safe, with a higher incidence of grade 3 diarrhea in the pertuzumab arm and more fatigue, asthenia, decreased appetite, vomiting, and dysgeusia.<xref rid="b181-cia-10-157" ref-type="bibr">181</xref> Trastuzumab and lapatinib were also evaluated in combination with endocrine therapy, and were found to have a clinical benefit.<xref rid="b182-cia-10-157" ref-type="bibr">182</xref>,<xref rid="b183-cia-10-157" ref-type="bibr">183</xref></p></sec><sec><title>Vascular endothelial growth factor-targeted therapy</title><p>Regarding antiangiogenic agents, a meta-analysis<xref rid="b184-cia-10-157" ref-type="bibr">184</xref> of the three randomized trials evaluating bevacizumab as first-line treatment in HER2-negative, metastatic BC, ie, E2100 (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT00028990), AVastin And DOcetaxel (AVADO) (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT00333775), and Regimens in Bevacizumab for Breast Oncology (RIBBON-1) (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT00262067), showed a benefit in PFS but not in OS. The benefit in PFS in the elderly (≥65 years) was less important than in younger patients (hazards ratio 0.67 for PFS in patients aged <65 years and 0.75 in patients aged ≥65 years). Concerns exist regarding safety, especially about cardiovascular events. In exploratory subanalyses of the AVADO trial,<xref rid="b185-cia-10-157" ref-type="bibr">185</xref> the MO19391 study (ClinicalTrials. gov identifier NCT00448591),<xref rid="b186-cia-10-157" ref-type="bibr">186</xref> and a large, multicenter, noninterventional German study,<xref rid="b187-cia-10-157" ref-type="bibr">187</xref> bevacizumab was well tolerated with no increase in the incidence of bevacizumab-related adverse events in patients aged over 65 years. In the subgroup analysis from the MO19391 study,<xref rid="b186-cia-10-157" ref-type="bibr">186</xref> the incidence of grade ≥3 hypertension was the only side effect reported more frequently in the elderly.</p><p>The ATHENA trial (MO19391, <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT00448591)<xref rid="b188-cia-10-157" ref-type="bibr">188</xref> is a large (2,251 patients), international, open-label study assessing first-line bevacizumab in combination with standard chemotherapy in HER2-negative metastatic BC. Data from the ATHENA trial were analyzed in the subgroup of elderly patients aged ≥70 years.<xref rid="b189-cia-10-157" ref-type="bibr">189</xref> Bevacizumab was combined with single-agent paclitaxel in 46% of older patients. Only hypertension and proteinuria were more common in older patients when compared with younger patients (6.9% versus 4.2%, respectively, for grade ≥3 hypertension; 4.0% versus 1.5%, respectively, for grade ≥3 proteinuria); and grade ≥3 arterial/venous thromboembolism events occurred in 2.9% versus 3.3%, respectively. Median time to progression was 10.4 months.</p></sec></sec><sec><title>Ongoing clinical trials</title><p>In the adjuvant setting, a randomized multicenter trial (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT0019301) comparing weekly docetaxel and CMF in the treatment of women with high-risk BC who are aged >65 years or are not candidates for anthracycline-based therapy has been completed.<xref rid="b190-cia-10-157" ref-type="bibr">190</xref> A randomized controlled trial is currently recruiting participants to evaluate trastuzumab without chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly BC patients (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT01104935).<xref rid="b191-cia-10-157" ref-type="bibr">191</xref> GERICO has developed a trial to evaluate the benefit of adjuvant chemotherapy on OS in patients aged 70+ years with pN0 or pN-positive, HR-positive/HER2-negative disease and a high genomic grade index assessed by reverse transcriptase polymerase chain reaction (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT01564056).<xref rid="b133-cia-10-157" ref-type="bibr">133</xref></p><p>In the metastatic setting, a randomized Phase II trial by the EORTC Elderly Task Force and Breast Cancer Group is currently recruiting participants (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT01597414).<xref rid="b192-cia-10-157" ref-type="bibr">192</xref> This trial will compare pertuzumab plus trastuzumab versus pertuzumab plus trastuzumab plus metronomic chemotherapy in the elderly with HER2-positive metastatic BC. After progression, patients will be given the option of receiving trastuzumab emtansine.</p><p>Concerning radiotherapy, a randomized Phase II trial is currently recruiting participants to compare partial versus WBRT in women aged ≥60 years operated with BCS (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT00892814).<xref rid="b193-cia-10-157" ref-type="bibr">193</xref> A multicenter, controlled, randomized, nonblinded, Phase III noninferiority study (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> identifier NCT01803958) is ongoing. This study was designed to evaluate whether partial hypofractionated and accelerated irradiation of the sole surgical cavity in patients suffering from BC with a low risk of local recurrence and who undergo conservative surgery is not inferior to postoperative irradiation with conventional fractionation of the entire breast as regards local control (incidence of ipsilateral recurrences as the prime event).<xref rid="b194-cia-10-157" ref-type="bibr">194</xref></p></sec><sec><title>Conclusion</title><p>To conclude, management of BC in the elderly is complex, firstly because this population is heterogeneous. Secondly, limited data are available, mainly because the aging population is poorly represented, especially in randomized controlled trials. Level 1 evidence data from randomized controlled trials in specific older populations (medically fit and medically frail patients) are urgently needed. We recommend a geriatric assessment when available to help the practitioner decide the best treatment for their patient. In this regard, the collaboration between oncology and geriatrics teams has resulted in the creation of oncogeriatric coordination units to facilitate access to treatment and coordinate the care of elderly patients suffering from cancer. Lastly, it is appropriate to have patient participation in decision-making, since elderly preferences often favor quality of life and independence.<xref rid="b195-cia-10-157" ref-type="bibr">195</xref> Yet, practitioners should inform their patients that undertreatment strongly decreases the prognosis of BC.<xref rid="b196-cia-10-157" ref-type="bibr">196</xref>,<xref rid="b197-cia-10-157" ref-type="bibr">197</xref></p><p>In the local setting, fit elderly and young women should be treated similarly. Frail patients should undergo surgery if possible. Primary endocrine therapy should only be offered to women with ER-positive tumors who are unfit for or refuse surgery and have a short estimated life expectancy less than 2–3 years. Minimally invasive techniques such as radiofrequency ablation are under evaluation. Management of the axilla in fit elderly women is the same as in younger women. Concerning radiotherapy, WBRT following BCS can only be omitted in frail patients with an obvious limited life expectancy and T1N0, ER-positive BC, as the burden of local recurrence is likely not to appear before the patient dies from another cause. Hypofractionated radiotherapy is an attractive validated option given that underuse of radiotherapy in the elderly may be related to the cost and inconvenience of a regimen protracted over several weeks. Accelerated partial breast irradiation is a promising alternative to WBRT, but the evidence is not sufficiently robust to recommend it as standard therapy. Regarding adjuvant medical therapy, omission of endocrine therapy is an option for patients with very low-risk tumors. For adjuvant chemotherapy, elderly patients should be given clear information on the benefit and risks of the therapy, given the fact that the toxicity is not negligible and the benefit is sometimes modest. Polychemotherapies are superior to capecitabine alone. The chemoregimens possible are CMF (with precautions), anthracyclines plus cyclophosphamide with a preference for liposomal anthracyclines, and docetaxel plus cyclophosphamide. Trastuzumab should be prescribed in combination with chemotherapy in HER2-positive BC in the absence of cardiac disease. In the metastatic setting, endocrine therapy is the preferred treatment in the absence of life-threatening or rapidly progressing disease. When chemotherapy is indicated, monochemotherapy, oral, and weekly regimens are preferred.</p></sec></body><back><fn-group><fn><p><bold>Disclosure</bold></p><p>The authors report no conflicts of interest in this work.</p></fn></fn-group><ref-list><title>References</title><ref id="b1-cia-10-157"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jemal</surname><given-names>A</given-names></name><name><surname>Bray</surname><given-names>F</given-names></name><name><surname>Center</surname><given-names>MM</given-names></name><name><surname>Ferlay</surname><given-names>J</given-names></name><name><surname>Ward</surname><given-names>E</given-names></name><name><surname>Forman</surname><given-names>D</given-names></name></person-group><article-title>Global cancer statistics</article-title><source>CA Cancer J Clin</source><year>2011</year><volume>61</volume><issue>2</issue><fpage>69</fpage><lpage>90</lpage><pub-id 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colspan="1">Hormone therapy</th><th valign="top" align="left" rowspan="1" colspan="1">Reference</th><th valign="top" align="left" rowspan="1" colspan="1">Age, median and range (years)</th><th valign="top" align="left" rowspan="1" colspan="1">Study design and population</th><th valign="top" align="left" rowspan="1" colspan="1">Efficacy</th><th valign="top" align="left" rowspan="1" colspan="1">Toxicity</th></tr></thead><tbody><tr><td rowspan="2" valign="top" align="left" colspan="1">Exemestane 25 mg orally once daily for 4 months</td><td valign="top" align="left" rowspan="1" colspan="1">Mlineritsch et al<xref rid="b198-cia-10-157" ref-type="bibr">198</xref></td><td valign="top" align="left" rowspan="1" colspan="1">71 (54–92)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II, 80 patients</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 34%<break></break>BCS 76%</td><td valign="top" align="left" rowspan="1" colspan="1">Grade 3 hot flushes 3.8%<break></break>Grade 2 bone pain 5%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Tubiana-Hulin et al<xref rid="b199-cia-10-157" ref-type="bibr">199</xref></td><td valign="top" align="left" rowspan="1" colspan="1">67.6 (52.1–92.2)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II, 45 patients</td><td valign="top" align="left" rowspan="1" colspan="1">ORR (clinical) 73.3%<break></break>ORR (ultrasonographic) 45.2%<break></break>BCS 57.1%</td><td valign="top" align="left" rowspan="1" colspan="1">Grade 1–2 toxicity 69.6%</td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">Anastrozole (1 mg once daily for 3 months) versus tamoxifen</td><td valign="top" align="left" rowspan="1" colspan="1">Cataliotti et al<xref rid="b200-cia-10-157" ref-type="bibr">200</xref> PROACT trial</td><td valign="top" align="left" rowspan="1" colspan="1">67.3 (48.7–91.5)</td><td valign="top" align="left" rowspan="1" colspan="1">Randomized, double-blind, multicenter, Phase III, 451 patients</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 39.5% (ultrasound measurements) and 50% (caliper measurements) BCS 43%</td><td valign="top" align="left" rowspan="1" colspan="1">Nausea 20.6%<break></break>Hot flushes 8.3%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Smith et al<xref rid="b201-cia-10-157" ref-type="bibr">201</xref> IMPACT trial</td><td valign="top" align="left" rowspan="1" colspan="1">73.2 (51.8–90.2)</td><td valign="top" align="left" rowspan="1" colspan="1">Randomized, double-blind, multicenter, Phase III, 330 patients</td><td valign="top" align="left" rowspan="1" colspan="1">Clinical ORR 37%<break></break>Ultrasound ORR 24%<break></break>BCS 44%</td><td valign="top" align="left" rowspan="1" colspan="1">Hot flushes 18%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Letrozole (2 mg once daily for 4 months) versus tamoxifen</td><td valign="top" align="left" rowspan="1" colspan="1">Eiermann et al<xref rid="b202-cia-10-157" ref-type="bibr">202</xref></td><td valign="top" align="left" rowspan="1" colspan="1">68</td><td valign="top" align="left" rowspan="1" colspan="1">Multinational, randomized, double-blind, Phase IIb–III, 324 patients</td><td valign="top" align="left" rowspan="1" colspan="1">Clinical ORR 55%<break></break>Ultrasound response 35%<break></break>BCS 45%</td><td valign="top" align="left" rowspan="1" colspan="1">Hot flushes 20%</td></tr></tbody></table><table-wrap-foot><fn id="tfn1-cia-10-157"><p><bold>Note:</bold> Grading based upon NCI-CTC (National Cancer Institute Common Toxicity Criteria).</p></fn><fn id="tfn2-cia-10-157"><p><bold>Abbreviations:</bold> ORR, objective response rate; BCS, breast-conserving surgery; PROACT, Pre-Operative “Arimidex” Compared to Tamoxifen trial; IMPACT, Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen trial.</p></fn></table-wrap-foot></table-wrap><table-wrap id="t2-cia-10-157" position="float"><label>Table 2</label><caption><p>Monochemotherapy regimens</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1">Chemotherapy regimens</th><th valign="top" align="left" rowspan="1" colspan="1">Dosage</th><th valign="top" align="left" rowspan="1" colspan="1">Reference</th><th valign="top" align="left" rowspan="1" colspan="1">Age, median and range (years)</th><th valign="top" align="left" rowspan="1" colspan="1">Study design and population</th><th valign="top" align="left" rowspan="1" colspan="1">Line</th><th valign="top" align="left" rowspan="1" colspan="1">Efficacy</th><th valign="top" align="left" rowspan="1" colspan="1">Toxicity</th></tr></thead><tbody><tr><td rowspan="3" valign="top" align="left" colspan="1">Pegylated liposomal doxorubicin</td><td valign="top" align="left" rowspan="1" colspan="1">40 mg/m<sup>2</sup> every 28 days</td><td valign="top" align="left" rowspan="1" colspan="1">Falandry et al<xref rid="b158-cia-10-157" ref-type="bibr">158</xref></td><td valign="top" align="left" rowspan="1" colspan="1">77 (71–89)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II, 60 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 20%<break></break>PFS 6.1 months<break></break>OS 15.7 months</td><td valign="top" align="left" rowspan="1" colspan="1">Febrile neutropenia 1.7%<break></break>Congestive heart failure 3.4%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">40 mg/m<sup>2</sup> every 28 days</td><td valign="top" align="left" rowspan="1" colspan="1">Green et al<xref rid="b203-cia-10-157" ref-type="bibr">203</xref></td><td valign="top" align="left" rowspan="1" colspan="1">72.3 (65–81)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase IV, 25 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">TTP 5.7 months<break></break>OS 20.6 months</td><td valign="top" align="left" rowspan="1" colspan="1">Cardiac events 12%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">20 mg/m<sup>2</sup> every 2 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">Basso et al<xref rid="b159-cia-10-157" ref-type="bibr">159</xref></td><td valign="top" align="left" rowspan="1" colspan="1">78 (70–93)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II, 32 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line (78.1%)</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 33.3%<break></break>TTP 10.3 months</td><td valign="top" align="left" rowspan="1" colspan="1">No cardiac event 9.4% treatment interruption for toxicity</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Oral Idarubicin</td><td valign="top" align="left" rowspan="1" colspan="1">5 mg/day for 21 consecutive days, every 4 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">Crivellari et al<xref rid="b204-cia-10-157" ref-type="bibr">204</xref></td><td valign="top" align="left" rowspan="1" colspan="1">75 (65–81)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 33 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First or second line</td><td valign="top" align="left" rowspan="1" colspan="1">PR 22%<break></break>SD 33%<break></break>TTP 3 months<break></break>OS 17 months</td><td valign="top" align="left" rowspan="1" colspan="1">Grade 4 neutropenia 6%<break></break>No cardiotoxicity reported<break></break>Two toxic deaths with 7.5 mg/day</td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">Capecitabine</td><td valign="top" align="left" rowspan="1" colspan="1">1,000 mg/m<sup>2</sup> twice daily</td><td valign="top" align="left" rowspan="1" colspan="1">Bajetta et al<xref rid="b161-cia-10-157" ref-type="bibr">161</xref></td><td valign="top" align="left" rowspan="1" colspan="1">73 (65–89)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 73 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line (93%)</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 34.9%<break></break>TTP 4 months</td><td valign="top" align="left" rowspan="1" colspan="1">2 toxic deaths with 1,250 mg/m<sup>2</sup><break></break>Low grade 3/4 AEs with 1,000 mg/m<sup>2</sup></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">1,000 mg/m<sup>2</sup> twice daily for 14 days every 3 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">De Sanctis et al<xref rid="b162-cia-10-157" ref-type="bibr">162</xref></td><td valign="top" align="left" rowspan="1" colspan="1">76 (65–88)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 75 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">Disease control rate 81.3%</td><td valign="top" align="left" rowspan="1" colspan="1">Grade 3 events: diarrhea (12%), hand–foot syndrome (8%), mucositis (8%)</td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">Vinorelbine</td><td valign="top" align="left" rowspan="1" colspan="1">30 mg/m<sup>2</sup>/week for 13 weeks and then every 2 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">Vogel et al<xref rid="b205-cia-10-157" ref-type="bibr">205</xref></td><td valign="top" align="left" rowspan="1" colspan="1">72 (60–84)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II, 56 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 38%<break></break>TTP 6 months</td><td valign="top" align="left" rowspan="1" colspan="1">Febrile neutropenia 11%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">70 mg/m<sup>2</sup> orally on days 1, 3, and 5, for 3 weeks every 4 weeks (maximum 12 cycles)</td><td valign="top" align="left" rowspan="1" colspan="1">Addeo et al<xref rid="b164-cia-10-157" ref-type="bibr">164</xref></td><td valign="top" align="left" rowspan="1" colspan="1">74 (70–84)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 34 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 38%<break></break>PFS 7.7 months<break></break>OS 15.9 months</td><td valign="top" align="left" rowspan="1" colspan="1">Febrile neutropenia 6%</td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">Paclitaxel</td><td valign="top" align="left" rowspan="1" colspan="1">80 mg/m<sup>2</sup> weekly for 3 weeks every 28 days</td><td valign="top" align="left" rowspan="1" colspan="1">Del Mastro et al<xref rid="b165-cia-10-157" ref-type="bibr">165</xref></td><td valign="top" align="left" rowspan="1" colspan="1">74 (70–87)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 46 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 53.7%<break></break>PFS 9.7 months<break></break>OS 35.8 months</td><td valign="top" align="left" rowspan="1" colspan="1">Unacceptable toxicity: 15.2% (febrile neutropenia, severe allergic reaction, and cardiotoxicity)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">80 mg/m<sup>2</sup> on days 1, 8, and 15 of a 28-day cycle (dose increase 90 mg/m<sup>2</sup> in absence of toxicity)</td><td valign="top" align="left" rowspan="1" colspan="1">Ten Tije et al<xref rid="b166-cia-10-157" ref-type="bibr">166</xref></td><td valign="top" align="left" rowspan="1" colspan="1">77 (71–84)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II, 26 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 38%<break></break>TTP 6.5 months</td><td valign="top" align="left" rowspan="1" colspan="1">Fatigue 67%<break></break>Neuropathy 39%</td></tr><tr><td rowspan="3" valign="top" align="left" colspan="1">Docetaxel</td><td valign="top" align="left" rowspan="1" colspan="1">36 mg/m<sup>2</sup> weekly for 6 consecutive weeks, followed by 2 weeks without treatment</td><td valign="top" align="left" rowspan="1" colspan="1">Hainsworth et al<xref rid="b168-cia-10-157" ref-type="bibr">168</xref></td><td valign="top" align="left" rowspan="1" colspan="1">74 (50–88)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 41 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line 75%<break></break>Second line 25%</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 36%<break></break>TTP 7 months<break></break>OS 13 months</td><td valign="top" align="left" rowspan="1" colspan="1">Severe neutropenia 0.4%<break></break>Grade 3/4 fatigue 20%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">36 mg/m<sup>2</sup> per week</td><td valign="top" align="left" rowspan="1" colspan="1">D’hondt et al<xref rid="b169-cia-10-157" ref-type="bibr">169</xref></td><td valign="top" align="left" rowspan="1" colspan="1">Frail and elderly patients (≥70 years)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 47 patients</td><td valign="top" align="left" rowspan="1" colspan="1">Median: 2 prior chemotherapy regimens</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 37%</td><td valign="top" align="left" rowspan="1" colspan="1">Febrile neutropenia 8.5%<break></break>Grade 3 neurotoxicity 2%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">36 mg/m<sup>2</sup> per week (starting dose of 26 mg/m<sup>2</sup> and dose escalating if no toxicity is advised)</td><td valign="top" align="left" rowspan="1" colspan="1">Hurria et al<xref rid="b170-cia-10-157" ref-type="bibr">170</xref></td><td valign="top" align="left" rowspan="1" colspan="1">75 (66–84)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase I, 20 patients</td><td valign="top" align="left" rowspan="1" colspan="1">Prostate, lung, and breast (50%) cancer</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">≥ Grade 3 58%<break></break>≥ Hematologic grade 3 16%<break></break>≥ Non-hematologic grade 3 53%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Eribulin</td><td valign="top" align="left" rowspan="1" colspan="1">1.4 mg/m<sup>2</sup> on days 1 and 8 of a 21-day cycle</td><td valign="top" align="left" rowspan="1" colspan="1">Muss et al<xref rid="b171-cia-10-157" ref-type="bibr">171</xref></td><td valign="top" align="left" rowspan="1" colspan="1">≥70 years, 79 patients</td><td valign="top" align="left" rowspan="1" colspan="1">Exploratory analysis from two Phase II studies and one Phase III randomized study, 827 patients</td><td valign="top" align="left" rowspan="1" colspan="1">Heavily pretreated MBC</td><td valign="top" align="left" rowspan="1" colspan="1">OS 12.5 months<break></break>PFS 4.0 months<break></break>ORR 10.1%<break></break>CBR 21.5%</td><td valign="top" align="left" rowspan="1" colspan="1">No overall effect of age on AEs</td></tr></tbody></table><table-wrap-foot><fn id="tfn3-cia-10-157"><p><bold>Abbreviations:</bold> AEs, adverse events; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; TTP, time to progression; PR, partial response; SD, stable disease; CBR, clinical benefit rate; MBC, metastatic breast cancer.</p></fn></table-wrap-foot></table-wrap><table-wrap id="t3-cia-10-157" position="float"><label>Table 3</label><caption><p>Comparison of chemotherapy regimens</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1">Chemotherapy regimen</th><th valign="top" align="left" rowspan="1" colspan="1">Dosage</th><th valign="top" align="left" rowspan="1" colspan="1">Reference</th><th valign="top" align="left" rowspan="1" colspan="1">Age, median and range (years)</th><th valign="top" align="left" rowspan="1" colspan="1">Study design and population</th><th valign="top" align="left" rowspan="1" colspan="1">Line</th><th valign="top" align="left" rowspan="1" colspan="1">Efficacy</th><th valign="top" align="left" rowspan="1" colspan="1">Toxicity</th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">PLD versus capecitabine</td><td valign="top" align="left" rowspan="1" colspan="1">6 cycles of PLD (45 mg/m<sup>2</sup> every 4 weeks) or 8 cycles of capecitabine (1,000 mg/m<sup>2</sup> twice daily, days 1–14 every 3 weeks)</td><td valign="top" align="left" rowspan="1" colspan="1">Smorenburg et al<xref rid="b160-cia-10-157" ref-type="bibr">160</xref></td><td valign="top" align="left" rowspan="1" colspan="1">75 (65–86)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, randomized, Phase III, 78 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">PFS 5.6 versus 7.7 months, <italic>P</italic>=0.11 OS 13.8 versus 16.8 months, <italic>P</italic>=0.59</td><td valign="top" align="left" rowspan="1" colspan="1">Comparable grade 3 AEs, no grade 4 AEs</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Epirubicin versus gemcitabine</td><td valign="top" align="left" rowspan="1" colspan="1">Epirubicin 35 mg/m<sup>2</sup> or gemcitabine 1,200 mg/m<sup>2</sup> on days 1, 8, and 15 of a 28-day cycle</td><td valign="top" align="left" rowspan="1" colspan="1">Feher et al<xref rid="b206-cia-10-157" ref-type="bibr">206</xref></td><td valign="top" align="left" rowspan="1" colspan="1">68 (59–91)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, randomized, Phase III, 397 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">Superiority of epirubicin TTP 6.1 versus 3.4 months, <italic>P</italic>=0.0001; OS 19.1 versus 11.8, <italic>P</italic>=0.0004; Independently assessed RR 40.3% versus 16.4%, <italic>P</italic><0.001, 186 and 183 evaluable patients)</td><td valign="top" align="left" rowspan="1" colspan="1">Both well tolerated</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Ixabepilone plus capecitabine versus capecitabine</td><td valign="top" align="left" rowspan="1" colspan="1">Ixabepilone 40 mg/m<sup>2</sup> every 3 weeks + oral capecitabine (1,000 mg/m<sup>2</sup> twice each day), or capecitabine alone (1,250 mg/m<sup>2</sup> twice each day)</td><td valign="top" align="left" rowspan="1" colspan="1">Vahdat et al<xref rid="b207-cia-10-157" ref-type="bibr">207</xref></td><td valign="top" align="left" rowspan="1" colspan="1">≥65</td><td valign="top" align="left" rowspan="1" colspan="1">Retrospective analysis, 251 patients</td><td valign="top" align="left" rowspan="1" colspan="1">Anthracycline and taxane pretreated</td><td valign="top" align="left" rowspan="1" colspan="1">PFS 5.5 versus 3.9 months<break></break>ORR 37% versus 19%<break></break>OS 13.9 versus 12.2 months</td><td valign="top" align="left" rowspan="1" colspan="1">Febrile neutropenia 10% (ixabepilone + capecitabine)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Paclitaxel versus docetaxel</td><td valign="top" align="left" rowspan="1" colspan="1">Weekly paclitaxel 80 mg/m<sup>2</sup> or weekly docetaxel 36 mg/m<sup>2</sup></td><td valign="top" align="left" rowspan="1" colspan="1">Beuselinck et al<xref rid="b208-cia-10-157" ref-type="bibr">208</xref></td><td valign="top" align="left" rowspan="1" colspan="1">Elderly or frail patients 63.7 (31–84)</td><td valign="top" align="left" rowspan="1" colspan="1">Randomized, multicentric, Phase II, 70 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line 17%<break></break>Second line 49%<break></break>Third line or more 34%</td><td valign="top" align="left" rowspan="1" colspan="1">PR 48% versus 38%, TTP 21.1 weeks versus 12.7 weeks<break></break>OS 55.7 weeks versus 32 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">More anemia and neurotoxicity for paclitaxel and more edema and fatigue for docetaxel</td></tr></tbody></table><table-wrap-foot><fn id="tfn4-cia-10-157"><p><bold>Abbreviations:</bold> ORR, objective response rate; PFS, progression-free survival; OS, overall survival; TTP, time to progression; PR, partial response; SD, stable disease; PLD, pegylated liposomal doxorubicin.</p></fn></table-wrap-foot></table-wrap><table-wrap id="t4-cia-10-157" position="float"><label>Table 4</label><caption><p>Polychemotherapy regimens</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1">Chemotherapy regimens</th><th valign="top" align="left" rowspan="1" colspan="1">Dosage</th><th valign="top" align="left" rowspan="1" colspan="1">References</th><th valign="top" align="left" rowspan="1" colspan="1">Age, median and range (years)</th><th valign="top" align="left" rowspan="1" colspan="1">Study design and population</th><th valign="top" align="left" rowspan="1" colspan="1">Line</th><th valign="top" align="left" rowspan="1" colspan="1">Efficacy</th><th valign="top" align="left" rowspan="1" colspan="1">Toxicity</th></tr></thead><tbody><tr><td rowspan="3" valign="top" align="left" colspan="1">Gemcitabine and vinorelbine</td><td valign="top" align="left" rowspan="1" colspan="1">Vinorelbine 25 mg/m<sup>2</sup> IV and gemcitabine 1,000 mg/m<sup>2</sup> IV on days 1 and 8 every 3 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">Dinota et al<xref rid="b209-cia-10-157" ref-type="bibr">209</xref></td><td valign="top" align="left" rowspan="1" colspan="1">69 (65–87)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 34 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 53%</td><td valign="top" align="left" rowspan="1" colspan="1">Grade 3/4 neutropenia 20%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Vinorelbine 25 mg/m<sup>2</sup> plus gemcitabine 1,000 mg/m<sup>2</sup> on days 1 and 8, every 3 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">Basso et al<xref rid="b210-cia-10-157" ref-type="bibr">210</xref></td><td valign="top" align="left" rowspan="1" colspan="1">74 (70–82)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II prematurely terminated for poor RR, 12 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 11.1%<break></break>TTP 3 months</td><td valign="top" align="left" rowspan="1" colspan="1">Grade 3 neutropenia 25%<break></break>Grade 3 anemia and grade 3 GI toxicity 25%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Gemcitabine 1,000 mg/m<sup>2</sup> and vinorelbine 25 mg/m<sup>2</sup> on days 1 and 8 every 3 weeks for a maximum of 6 cycles</td><td valign="top" align="left" rowspan="1" colspan="1">Dong et al<xref rid="b172-cia-10-157" ref-type="bibr">172</xref></td><td valign="top" align="left" rowspan="1" colspan="1">73 (65–84)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 51 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line (54.9%)</td><td valign="top" align="left" rowspan="1" colspan="1">RR 33.3%<break></break>PFS 6.2 months<break></break>OS 17 months</td><td valign="top" align="left" rowspan="1" colspan="1">Febrile neutropenia 4% One toxic death because of GI hemorrhage</td></tr><tr><td rowspan="2" valign="top" align="left" colspan="1">PLD plus vinorelbine</td><td valign="top" align="left" rowspan="1" colspan="1">PLD 40 mg/m<sup>2</sup> plus vinorelbine 25 mg/m<sup>2</sup> IV on day 1 and oral vinorelbine 60 mg/m<sup>2</sup> on day 15</td><td valign="top" align="left" rowspan="1" colspan="1">Addeo et al<xref rid="b211-cia-10-157" ref-type="bibr">211</xref></td><td valign="top" align="left" rowspan="1" colspan="1">71 (65–82)</td><td valign="top" align="left" rowspan="1" colspan="1">Phase II, 34 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 50%<break></break>OS 13 months<break></break>TTP 8 months</td><td valign="top" align="left" rowspan="1" colspan="1">Neutropenia grade 3/4 26% Febrile neutropenia 8.8%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">PLD 40 mg/m<sup>2</sup> IV on day 1 and vinorelbine 30 mg/m<sup>2</sup> IV on days 1 and 15 every 4 weeks</td><td valign="top" align="left" rowspan="1" colspan="1">Mlineritsch et al<xref rid="b212-cia-10-157" ref-type="bibr">212</xref></td><td valign="top" align="left" rowspan="1" colspan="1">68 (60–82)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II, 42 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 36%<break></break>TTP 4 months<break></break>OS 24 months</td><td valign="top" align="left" rowspan="1" colspan="1"></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Oral capecitabine and vinorelbine</td><td valign="top" align="left" rowspan="1" colspan="1">6 cycles: capecitabine 750 mg/m<sup>2</sup> bid, days 1–14 every 21 days Vinorelbine 45 mg/m<sup>2</sup>, days 1 and 8<break></break>Dose escalation after 3 cycles depending on tolerance (capecitabine 1,000 mg/m<sup>2</sup> bid, days 1–14 and vinorelbine 60 mg/m<sup>2</sup>, days 1 and 8)</td><td valign="top" align="left" rowspan="1" colspan="1">Rousseau et al<xref rid="b173-cia-10-157" ref-type="bibr">173</xref></td><td valign="top" align="left" rowspan="1" colspan="1">75.5 (69–86)</td><td valign="top" align="left" rowspan="1" colspan="1">Multicenter, Phase II trial, 80 patients</td><td valign="top" align="left" rowspan="1" colspan="1">First line</td><td valign="top" align="left" rowspan="1" colspan="1">ORR 8.6% 1-year PFS 9.8%<break></break>1-year OS 54.9%</td><td valign="top" align="left" rowspan="1" colspan="1">Febrile neutropenia 1.3% grade 3/4 hematological toxicity: 17.9%<break></break>Grade 3/4 GI toxicity 7.7%</td></tr></tbody></table><table-wrap-foot><fn id="tfn5-cia-10-157"><p><bold>Abbreviations:</bold> ORR, objective response rate; PFS, progression-free survival; OS, overall survival; TTP, time to progression; PLD, pegylated liposomal doxorubicin; RR, response rate; GI, gastrointestinal; IV, intravenous; bid, twice daily.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour 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