Taxanes in the Treatment of Breast Cancer: Have We Better Deﬁned Their Role in Older Patients? a Position Paper from a SIOG Task Force ⇑ L

Cancer Treatment Reviews 43 (2016) 19–26

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Cancer Treatment Reviews

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Anti-Tumour Treatment Taxanes in the treatment of breast cancer: Have we better deﬁned their role in older patients? A position paper from a SIOG Task Force ⇑ L. Biganzoli a, , M. Aapro b, Sibylle Loibl c, Hans Wildiers d, Etienne Brain e a Nuovo Ospedale Santo Stefano – Istituto Toscano Tumori, Prato, Italy b Multidisciplinary Oncology Institute, Clinique de Genolier, Switzerland c German Breast Group, Sana-Klinikum Offenbach, Germany d University Hospitals Leuven, Leuven, Belgium e Institut Curie – Hôpital René Huguenin, Saint-Cloud, France article info abstract

Article history: Along with anthracyclines, taxanes are the most active cytotoxics in breast cancer (BC). Balancing efficacy Received 1 October 2015 against toxicity in older patients with reduced physiological reserves and significant comorbidities is Received in revised form 24 November 2015 both important and difficult. This is especially so given the under-representation of elderly patients in Accepted 25 November 2015 major trials and a consequent lack of evidence for drug, dose and schedule. However, BC is frequent in elderly women, who are a growing proportion of the population. Careful consideration of their care is therefore imperative. Treatment that can cure or extend the duration and quality of life should not be Keywords: restricted by age, but needs to be tailored to the circumstances of elderly patients. In adjuvant use, taxane Breast cancer toxicity in older women is greater than in their younger counterparts, limiting its sequential combination Elderly Docetaxel with anthracyclines for high-risk disease unless patients are in very good health. More frequently taxanes Paclitaxel are used alone (weekly paclitaxel, three-weekly docetaxel) or combined with cytotoxics other than Nab-paclitaxel anthracyclines (e.g. docetaxel plus cyclophosphamide) to reduce cardiac risk, especially in HER-2- Taxanes positive patients who may develop additional trastuzumab-related cardiac events. In elderly patients with metastases, weekly paclitaxel and three-weekly docetaxel are among the cornerstones of treatment, with generally acceptable toxicity. Three-weekly docetaxel at the approved dose of 100 mg/m2 is not appropriate for the elderly. Nab-paclitaxel has efficacy comparable with solvent-based taxanes without need for steroid premedication but has been little studied in older BC patients. A head-to-head comparison with weekly paclitaxel favoured the solvent-free formulation for pathologic response, but those studied were a general adult population. Compared with early stage disease, choice of taxane and regimen in the metastatic setting relies even more on availability and preferences with regard to schedule, toxicity profile and cost, especially for recently developed formulations. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction risk of dying from BC increases with age [3], despite the greater contribution from competing causes of mortality. The median age at diagnosis of breast cancer (BC) is 61 years, A probable explanation is that age strongly affects the treat- 41% of cases occur in women aged 65 and over, and 21% of new ment received. Elderly patients are less likely than their younger diagnoses are in women aged over 75 [1]. The median age of those counterparts to have full diagnostic assessment and post- who die of the disease is 68. BC is in large part a disease of the operative radiotherapy [4]. And they are less likely to be treated elderly [2]. Breast cancers in the elderly are more likely to be indo- with full courses of chemotherapy of proven efficacy. Hence lent than in younger women, and the prevalence of hormone increasing age is not only a risk factor for the development of receptor-positive and HER2-negative tumours is higher. Yet the breast cancer but also for its undertreatment [5]. Geriatric assessment, preceded if necessary by a short geriatric screening test, can ⇑ contribute to evaluation of the general health status of cancer Corresponding author at: Dept of Medical Oncology, Nuovo Ospedale di Prato, patients and leads to therapy that is more adapted to individual Istituto Toscano Tumori, via Suor Niccolina, Infermiera, 20, 59100 Prato, Italy. Tel.: +39 0574 802520. needs. Such assessment is feasible, reveals previously unknown E-mail addresses: [email protected], [email protected] problems, and potentially influences treatment decisions. General (L. Biganzoli). http://dx.doi.org/10.1016/j.ctrv.2015.11.009 0305-7372/Ó 2015 Elsevier Ltd. All rights reserved. 20 L. Biganzoli et al. / Cancer Treatment Reviews 43 (2016) 19–26 issues concerning management of the older cancer patient, includ- of comorbidities such as cardiovascular disease and diabetes. This ing the role of geriatric assessment, are considered elsewhere [6,7]. is evident, for example, when data from the ATHENA study in One reason for undertreatment may be the underestimation of metastatic breast cancer (MBC) are analysed by age: active hyper- patients’ fitness and their life expectancy if free from cancer. In tension was evident in 49% of patients aged 70 or above but in only fact, the median life expectancy of a seventy year old woman is fif- 20% of those who were younger; and diabetes had been diagnosed teen years, and ten years at the age of eighty [8]. Another reason is in 11% of the older group, but in only 5% of younger patients [20]. uncertainty about the efficacy of treatment since older patients are The increased frequency of comorbidities was reflected in baseline substantially underrepresented in clinical trials [9]. For example, medication and, as a consequence, a greater risk of drug interac- only 16% of patients enrolled in the pivotal trials of adjuvant tions. These considerations require a practical and individualized trastuzumab were aged 60 years or older [10,11]. approach to therapy based on comprehensive geriatric assessment Even when the results of major trials are aggregated, data may (CGA) including both physical and cognitive function and the be insufficient to arrive at clear conclusions regarding the elderly. availability of social support. Thus, in the most more recent meta-analysis, the Early Breast Can- One important aspect of treating elderly BC patients is the cer Trialists’ Collaborative Group (EBCTCG) assessed the long-term increased risk of anthracycline-induced cardiotoxicity. According outcome of 100,000 women included in more than a hundred ran- to a retrospective review of data from 630 patients involved in domised trials [12]. In studies that had involved taxane or three phase III studies (two in BC), exposure to a cumulative dose anthracycline-based regimens, the proportional reductions in risk of 550 mg/m2 doxorubicin was associated with a cumulative 26% of recurrence or death from breast cancer were little affected by risk of drug-related congestive heart failure (CHF) [21]. Indepen- age. Again, relatively few women aged over 70 were enrolled. dent of performance status and comorbidities, older age increased The EBCTCG concluded that elderly women appeared to have the risk of cardiotoxicity. Moreover, data from more than forty experienced as great a benefit in recurrence and mortality risk as thousand women aged 66–80 years show that CHF induced by younger patients, based on relative risk reduction. However, abso- anthracyclines occurs at a steady rate up to ten years after expo- lute gain – the goal that is understood and sought by patients – sure in the adjuvant context. At ten years, the CHF rate among may be quite different. women who had had no adjuvant chemotherapy was 29%. The fig- Although still providing a statistically significant reduction in ure among women with non-anthracycline chemotherapy was relative risk, chemotherapy would very likely be declined by most 32.5%, while 38.4% of women who had been treated with anthracy- elderly patients with a T1 N0 breast tumour since the 1–2% abso- clines had had a diagnosis of CHF [22]. lute additional benefit brought by the addition of chemotherapy This has led to calls for cardiac risk factors to be more effectively to endocrine therapy – while it should be discussed – would not identified prior to treatment, for more rigorous monitoring of car- justify the likely impact on functional status and independence. diac function, for protocols that encourage early intervention when In part, this goes against epidemiological and population-based likely problems are identified, and for the consideration of poten- research suggesting that, even when data are adjusted for stage of tially less cardiotoxic anthracycline formulations or agents [23]. disease, the wider population of older women with BC has bene- In this context, there is interest in using taxanes instead of fited less than younger women from survival improvements due anthracyclines since cardiac toxicity is generally not an issue. to recent advances in treatment. This is true both for Europe [13] and in the United States [14]. In the USA, incidence-based mortal- Taxanes in the elderly ity rates among women aged less than 70 years fell 38% between 1990 and 2003 for those with ER-positive tumours. For those with Along with anthracyclines, taxanes are the most effective ER-negative tumours, the mortality reduction was 19%. However, agents in BC. They are inhibitors of microtubule dynamics, and for women aged 70 and over with ER-positive tumours the mortal- the two leading compounds are solvent-based. Both are associated ity reduction was only 14%; and older women with ER-negative with major toxicities such as myelosuppression and neuropathy tumours showed no decline in mortality over the relevant period. which may restrict their use, particularly in elderly patients; and Jatoi et al. concluded that we need increased efforts to improve the need for steroid premedication hinders their use in patients outcome in the elderly. with diabetes. Other less threatening side-effects can adversely General aspects of this problem have been addressed by the affect patients, particularly the elderly, who are more concerned National Comprehensive Cancer Network [9] and in joint recom- about quality than quantity of life. For example, despite use of mendations from the International Society of Geriatric Oncology the cold cap, alopecia remains psychosocially damaging, especially (SIOG) and the European Society of Breast Cancer Specialists with docetaxel [24]. Our knowledge about optimal drug, dose and (EUSOMA) [15,16]. The present paper has a more specific remit: schedule in older women with BC is limited since relatively few consideration of the potential that taxanes have to improve the such patients have been included in key trials and data are not gen- balance of efficacy versus toxicity in the elderly breast cancer erally analyzed by age. Nevertheless reviews in 2004 and 2009 patient. considered whether docetaxel and paclitaxel (in standard formulations) could be used in a way that maximized their therapeutic index [25,26]. Older breast cancer patients: general considerations

In contrast to chronological ageing, biological ageing is not uni- Pharmacokinetics form. Cancer patients aged 75 can be as fit as those decades younger, and as eager to maximize their chances of long-term sur- Of particular relevance to the pharmacokinetics (PK) of taxanes vival. At the age of 75, a breast cancer patient who was otherwise in the elderly are the potential for patients to be hypoalbuminaemic, in good health would have a life expectancy of over ten years [17]. which may increase the concentration of highly protein-bound However, there is no doubt that aging is associated in many drugs, and decreased cytochrome P450 activity in the ageing liver, patients with decreased physiological reserves and altered phar- which may limit their metabolism. In relation to the toxicity macokinetics which may reduce the tolerability of cytotoxic of three-weekly (q3w) docetaxel, data suggest that the increased chemotherapy and enhance the risk of treatment-related adverse risk of febrile neutropenia with age (16% in patients 65 years old events (AEs) [18,19]. There is also a clear increase in the likelihood or older compared with 0% in their younger counterparts) is not L. Biganzoli et al. / Cancer Treatment Reviews 43 (2016) 19–26 21 due to altered PK but to increased bone marrow sensitivity [27]. This were worse, and there was no difference in outcome [39]. The view is supported by the study of Minami et al. in non-small cell occurrence of fatal events in ELDA feeds the debate about taxanes lung cancer [28]. Data are less clear for paclitaxel for which being aggressive cytotoxics, irrespective of schedule. there is great inter-patient variability in clearance [29]. In relation to weekly paclitaxel in BC, three trials (all of weekly Moreover clearance of its unbound form is less in patients older 80 mg/m2 and all in metastatic or advanced disease) provide rele- than 70 years, although this seems to have no impact on rates of vant data [40–42]. In the Perez et al. study, grade 3–4 neutropenia neutropenia [30]. occurred in 15% of patients aged 65 years or older, which was the same proportion as in younger patients. In the study by ten Tije The potential importance of schedule et al. weekly paclitaxel was again relatively well tolerated, but 32% of patients discontinued because of fatigue. In the Del Mastro Overall, studies of docetaxel and paclitaxel do not suggest the study, cardiotoxicity emerged as an unexpected problem, and this need for dose modification for reasons of age alone. In the case did not seem to be related to prior exposure to anthracyclines. of docetaxel, this applies only to the 75 mg/m2 q3w dose and However the majority of data in the adult population do not sug- schedule used in lung, prostate and some breast regimens. Of note, gest that weekly paclitaxel is associated with cardiac failure. with rates of febrile neutropenia often approximating 15–20%, this In relation specifically to the elderly or frail, Beuselinck et al. 75 mg/m2 dose requires primary prophylaxis with granulocyte- carried out a randomized phase II trial of weekly paclitaxel vs colony stimulating factor [31]. Much greater prudence is war- weekly docetaxel in 70 metastatic BC patients considered unsuited ranted with the higher 100 mg/m2 dose used in some common to q3w regimens, including 28 aged P 70 [43]. Median OS was adjuvant chemotherapy schedules. Although approved and consid- longer with paclitaxel (56 vs 32 weeks). Anaemia and neurotoxic- ered standard for adults in many European countries, this dose is ity were more frequent with paclitaxel and oedema and fatigue difficult to administer to the majority of older patients. more frequent with docetaxel, though the incidence of grade 3 or In the 2000s, the concept of dose-density and attempts to cir- greater toxicity was never higher than 10%. Weekly administration cumvent side-effects that were reported to be peak-dependent of both drugs was considered tolerable in these less fit patients. led to the development of weekly schedules. Biganzoli et al. This relatively recent study therefore supported the conclusion of reviewed four randomized trials of weekly vs q3w taxanes in BC an earlier review that weekly taxanes are a reasonable option for [26]: two studies involved docetaxel in metastatic breast cancer older patients with BC [25]. (MBC), [32,33] one paclitaxel in MBC, [34] and one docetaxel and paclitaxel as alternatives following standard adjuvant doxorubicin Other compounds plus cyclophosphamide [35]. Taking the studies overall, data suggest that weekly paclitaxel Toxicity issues with the two main taxanes have led to the has a better haematological safety profile, although this schedule search for other formulations, especially those, such as albumin- is associated with an increased incidence of neuropathy both in bound paclitaxel (nab-paclitaxel), which might avoid need for the advanced stages [34] and early stages [35]. Weekly paclitaxel also allergenic solvent vehicle Cremophor EL [44,45]. Such formulation seems more effective in both the adjuvant and metastatic settings might also have the advantage of faster clearance compared with and represents the recommended schedule also in the elderly. solvent based agents, as shown in a randomized crossover pharma- Strict monitoring of neurotoxicity is recommended this group. cokinetic study [46]. Good tolerability across age groups has been Weekly docetaxel might be less myelosuppressive than q3w reported [47]. Other initiatives include the use of a cationic administration, but non-haematological complications and poor liposome-encapsulated formulation for paclitaxel. This has promis- adherence can be frequent, and weekly docetaxel in the adjuvant ing preliminary activity and allows targeting of tumour endothe- setting is less effective than three-weekly administration [36]. lium, but the issue of hypersensitivity reactions would need to Hence this schedule is little used. be resolved [48]. The trials considered above were not confined to elderly Although cabazitaxel has not been investigated in depth in BC, patients. However, based on the suggestion that weekly scheduling results were encouraging with a weekly schedule in relatively unfit might improve the balance of benefit versus toxicity, several sub- metastatic, castration-resistant prostate cancer patients progress- sequent studies of weekly taxanes were conducted specifically in ing after docetaxel. There were no serious safety concerns older women with BC. [49,50]. Given potential clinical and pharmacokinetic advantages Hainsworth et al. investigated weekly docetaxel in elderly BC over its predecessor, docetaxel, these phase II data would support patients with advanced disease [37]. Patients with a median age its investigation also in elderly BC patients. of 74 years and median PS of 1 received 36 mg/m2 docetaxel for six weeks followed by two weeks off. Severe neutropenia occurred in only 0.4% of 448 courses but cumulative fatigue (which was Taxanes according to setting related to total dose administered) led to treatment discontinuation in nine of 41 patients. Metastatic disease The French Unicancer GERICO group investigated an alternative biweekly docetaxel regimen (50 mg/m2 q2w) in women at least Among available options for MBC, selection of the most appro- 70 years old with MBC [38]. This regimen was not feasible: after priate in an individual case should take into account both the like- inclusion of 27 patients, there was an unacceptably high rate of lihood of meaningful response and the risk of specific AEs. The fatal events, potentially related to increased steroid-induced SIOG-EUSOMA guidelines suggest that older MBC patients benefit immunodeficiency. from chemotherapy to much the same extent as younger patients The most important safety data published so far using such a [16]. Single-agent chemotherapy is generally preferred to combi- weekly docetaxel schedule in the elderly come from the recently nation regimens since polychemotherapy is usually more toxic published Italian ELDA phase III trial. In comparison with standard and provides, at most, limited survival gain. Preference should be CMF (cyclophosphamide, methotrexate and 5-fluorouracil), weekly given to chemotherapy agents and schedules with better safety docetaxel caused less haematological toxicity, nausea and mucosi- profiles. tis; but allergy, fatigue, hair loss, onychopathy, dysgeusia, diar- These considerations apply to taxanes for elderly patients. As in rhoea, abdominal pain, neuropathy, cardiac and skin toxicity younger patients, weekly paclitaxel is one of the most widely used 22 L. Biganzoli et al. / Cancer Treatment Reviews 43 (2016) 19–26

MBC regimens. Docetaxel can also be used either weekly or q3w, vs 125 mg/m2 nab-paclitaxel in breast cancer patients aged 65 although more often with the standard q3w schedule, and prefer- and above [59]. Preliminary data in 44 patients suggest that both ably not at the high 100 mg/m2 dose. One of the main issues is the doses can safely be administered to elderly patients. The most need to avoid non-haematological toxicities such as neurotoxicity, frequently reported adverse events are fatigue and neurotoxicity, which is clinically significant from grade 2 and can jeopardize the and only one patient to date has experienced grade 4 non- functional status central to care of the elderly. haematological toxicity. The primary composite endpoint combi- In a combined analysis of two Cancer and Leukemia Group B nes progressive disease or death and functional decline monitored (CALGB) studies (9324 and 9840), Lichtman et al. found that every cycle by ADL and IADL. This reflects the SIOG and EORTC rec- women over 65 years receiving paclitaxel as either first- or ommendations regarding the methodology of clinical trials in second-line therapy for MBC were no less likely than their younger elderly patients [60]. As a general comment, nab-paclitaxel might counterparts to experience tumour response and survival benefit be an alternative in this setting, especially in patients in whom [51]. However, elderly patients in the second-line setting were there is concern about allergic reactions and/or use of steroids. considerably more likely than younger women to experience grade P 3 neurotoxicity. Early stage breast cancer The impact of specific AEs such as sensory neuropathy will vary from one woman to another and it may be helpful to assess their The NCCN Task Force on BC in the older woman concluded that impact on function using the Instrumental Activities of Daily Living there is no clear preference for any particular adjuvant regimen. (IADL) or Activities of Daily Living (ADL) scales and to monitor But they suggested caution with anthracyclines; use of less myelo- patients closely while they are on treatment [52]. The fatigue suppressive therapies; careful evaluation of renal and hepatic func- commonly associated with weekly docetaxel has a particularly tion; possible benefits of weekly dosing; and early use of myeloid negative impact on functioning in older patients [53]. Treatment growth factors [9]. with conventional solvent-based taxanes (weekly paclitaxel or Certain trials which enrolled predominantly younger women q3w docetaxel) is likely to be feasible in the majority of elderly include sufficient elderly patients to allow subgroup analyses by patients with MBC, provided that function is closely monitored. age. However, exclusion criteria other than age mean that the older Nab-paclitaxel might prove to be both a practical and effective patients enrolled were more fit than the wider population of older alternative to standard taxanes [54]. In a randomized phase III women with BC. Even so, Muss et al. showed increased haemato- study comparing 3 weekly paclitaxel with 3 weekly nab- logical toxicity and treatment-related deaths among older patients paclitaxel, response rate (RR) and progression-free survival (PFS) in the CALGB trials [61]. Adjuvant regimens that are considered were significantly higher with nab-paclitaxel [45]. In a randomized standard in young patients are not always well tolerated by the phase II study comparing q3w docetaxel, q3w nab-paclitaxel and elderly. However, the attempt to provide a less toxic alternative, two doses of weekly nab-paclitaxel (given over three of four eg by using capecitabine, illustrates the potential trade-off weeks), PFS was significantly longer with weekly 150 mg/m2 between tolerability and efficacy. The survival benefit of standard nab-paclitaxel than with docetaxel 100 mg/m2 q3w (12.9 vs doxorubicin plus cyclophosphamide (AC) or CMF was greater than 7.5 months). The incidence of grade 3 neuropathy was higher with with oral capecitabine (3-year OS 91% vs 86%) in a selected popu- 3 weekly nab-paclitaxel than with standard paclitaxel in the first lation of older patients with stage I-IIIB breast cancer [62]. The ICE- study [45] and similar with the two agents in the second one 1 study also suggested that adjuvant capecitabine has no role: [55]. It is worth noting that the median time to resolution of grade capecitabine compared against no chemotherapy in patients 3 neuropathy to a lesser grade was shorter with nab-paclitaxel receiving ibandronate found no difference in PFS or OS [63]. than with the conventional taxanes [45,55]. In MBC, there is no comparison between single-agent weekly Might taxanes be helpful in elderly EBC? nab-paclitaxel and weekly paclitaxel. The single head-to-head comparison we have favours the solvent-free formulation, but this Jones et al. were the first to report the potential benefit of adju- is in the neoadjuvant setting, in the general adult population, and vant taxanes in elderly patients (P65 years), based on the based on pathologic response [56]. Of note, the recently published unplanned sub-group analysis of the 9735 trial which compared CALGB 40502/NCCTG N063H (Alliance) phase III trial compared a non-anthracycline regimen of docetaxel plus cyclophosphamide single agent weekly (3 or 4 weeks) nab-paclitaxel 150 mg/m2 or (TC) versus AC [64]. At seven years, both younger and older ixabepilone 16 mg/m2 versus paclitaxel 90 mg/m2, but with the patients assigned to TC (N = 428 and 78 respectively) were more addition of bevacizumab, which is known to have an impact on likely to be free of disease than those assigned to AC. Both age toxicity [57]. The arm with the semisynthetic analogue of epothi- groups also showed an OS advantage for TC. Elderly women were lone B yielded a PFS benefit inferior to paclitaxel, while the nab- more likely to experience febrile neutropenia (FN) with TC than paclitaxel arm was not superior. The addition of bevacizumab hin- with AC (8% vs 4%). The corresponding figures in younger patients ders the interpretation of safety data especially given the high were 4% and 2%. However, it was unclear how many patients doses used weekly in the two experimental arms. Haematological received prophylactic oral antibiotics and/or G-CSF. In the elderly toxicity was higher with nab-paclitaxel. Although statistically dif- cohort, grade 3–4 anaemia was more common with AC than TC ferent across arms, grade P 2 neuropathy was frequent in all (5% vs <1%). The three late deaths without relapse all occurred in (range 46–54%), and relative dose intensity disadvantaged nab- the AC group. The authors concluded that these data supported paclitaxel with higher discontinuation and dose reduction rates. increased use of the non-anthracycline regimen in older women, No study has prospectively evaluated nab-paclitaxel in the especially those with lower risk disease. older MBC population and this makes it even more difficult to draw To further document TC in elderly women, Freyer et al. reported any firm conclusion for elderly patients. However, the single post a retrospective study of 110 women aged over 70 who had com- hoc analysis of patients aged 65 and over enrolled in the first pleted TC, the majority receiving 75 mg/m2 docetaxel and two MBC trials [45,55] suggests that weekly nab-paclitaxel is safe, 600 mg/m2 cyclophosphamide [65]. Seventy-one percent had at effective and appropriate first-line therapy [58]. least one comorbidity at diagnosis. During treatment, 5% of Prospective trials focused on elderly patients are needed to patients had FN and the rate of grade 3–4 non-haematological tox- better define the role and optimal dose of nab-paclitaxel in this icities was 5% or less. G-CSF had been given as primary prophylaxis population. The current EFFECT trial is investigating weekly 100 in 52% of patients. In these circumstances, Freyer et al. regard TC as L. Biganzoli et al. / Cancer Treatment Reviews 43 (2016) 19–26 23 a safe regimen for BC patients aged over 70 but suggest that clinical focused on safety), rates of invasive disease-free survival were trials are required to further evaluate adjuvant taxanes in the equivalent between the treatments at 48 months. In the experi- elderly. mental arm, grade 3–4 toxicity was significantly more frequent However the true rate of FN with TC in the elderly is debated. (59% vs 19%) and fewer patients completed treatment (65% vs Younus et al. reviewed the records of 134 patients (median age 93%). Haematological toxicity was more frequent with EC/CMF 62) and concluded that adjuvant TC in community practice causes and non-haematological toxicity more frequent with nab- a much higher rate of FN (20%) than is suggested by the trial liter- paclitaxel plus capecitabine. In the context of the elderly, the ature [66]. Forty percent of patients in this series were 65 or older, important feature of this study was that the largest influence on and their risk of FN was 26%. These data strongly support primary tolerability was the regimen used, and not comorbidity, albumin prophylaxis with G-CSF when using TC in the elderly, in agreement and status on geriatric assessment. with EORTC guidelines, where the FN risk is either greater than 20% This lack of conclusive data for the elderly population might be or between 10% and 20% in the presence of other risk factors resolved by the ongoing WAFE trial comparing single agent nab- including age of 65 years and above [31]. paclitaxel against epirubicin in women with early BC who are In the ELDA trial, safety profiles differed between CMF and elderly or unfit for a three-weekly polychemotherapy regimen. weekly docetaxel, but DFS and OS were similar in the two groups [39]. Quality of life was worse with docetaxel, as were most non- haematological side effects. Age, functional impairment, number Taxanes in HER2-positive disease of comorbidities and docetaxel treatment were independently associated with severe non-haematological toxicity in this popula- HER2-positive (HER2+) disease must be considered separately. tion aged 65–79 years. Based on docetaxel’s safety profile, negative The addition of trastuzumab to chemotherapy has dramatically impact on QoL and the absence of superior efficacy over standard improved outcome in BC, both in metastatic and adjuvant settings. CMF, weekly docetaxel cannot be considered a standard adjuvant However, this has been at the cost of increased cardiotoxicity. This regimen in older breast cancer patients [39,66,67]. is perhaps less of an issue in MBC where many non-cardiotoxic Fewer data are available for adjuvant paclitaxel in the elderly. cytotoxics are available for combination with trastuzumab. How- Single agent paclitaxel was compared with AC in CALGB 40101 ever, more caution is needed in the adjuvant setting where age is [68]. Paclitaxel was less toxic but the trial did not show non- a proven risk factor for trastuzumab cardiotoxicity and options inferiority to AC: single-agent paclitaxel has not superseded AC. are limited [72–75]. Use of an anthracycline-free regimen could Patients treated with standard q3w or dose-dense q2w paclitaxel be important in older patients with low-intermediate risk of greatly exceeded those treated with the optimal weekly schedule. relapse or who present with comorbidities that could increase Outcome using this more attractive schedule therefore remains cardiotoxicity. unclear, especially for elderly patients. In an open-label phase II study, predominantly in node-negative Helpful information can be derived from combined data analy- patients, the non-anthracycline TC combination with trastuzumab ses that allow extraction of data dealing specifically with the achieved a two-year DFS of 97.8% (95% CI 96.0–98.8) and overall elderly. Loibl et al. assessed data from more than four thousand survival of 99.2% (95% CI97.8–99.7) [76]. Cardiac dysfunction was patients in four randomised studies of anthracycline and taxane- seen in only 6% of patients and was generally reversible. Although containing chemotherapy between 1999 and 2005 (two in the the median age of patients entered was 55 years, women as old as adjuvant setting and two neoadjuvant) [69]. Treatment variables 75 were included. and toxicity were analysed by age: 3160 patients were less than The regimen of docetaxel plus carboplatin plus trastuzumab 60 years old, 645 were aged 60–64 years, and 422 were 65 and (TCH) must also be considered for elderly patients since it too does over. In the latter group, the median age was 67. not contain anthracyclines. Efficacy is similar to standard Dose delays and reductions and discontinuation of treatment anthracycline-taxane regimens while cardiac toxicity is consider- increased with age. Thus, among patients aged under 60, 9% had ably less [77]. However, the study had an upper age cut-off of dose reductions, compared with 14% of those aged 65 and over. 70 years, so there are no data in truly elderly patients. Although Treatment discontinuation occurred in 12% vs 19%. Grade 3–4 neu- theoretically adjusted to renal function, the high dose of carbo- tropenia affected 47% of patients under 60 but 57% of patients who platin (AUC 6) in combination with docetaxel would probably were 65 and over. However, the risk of FN showed little increase make this schedule difficult for the majority of older patients. with age. Older patients were more likely than their younger coun- The combination of weekly paclitaxel and trastuzumab in node- terparts to experience fatigue and gastrointestinal AEs. negative HER2+ disease has also been studied [78]. Although this Loibl et al. conclude that (neo)adjuvant chemotherapy in the was a single-arm phase II with no specific focus on the elderly pop- elderly is feasible in patients eligible for an anthracycline/taxane ulation, the relapse rate was encouragingly low (three-year DFS regimen, that its toxicity can be reduced by sequential administra- 98.7%), and the combination relatively non-toxic. Among 406 tion of anthracyclines and taxanes and by prophylactic treatment, patients entered, there have been two cases of symptomatic CHF. and that weekly paclitaxel may be preferable to docetaxel in a Weekly paclitaxel and trastuzumab might therefore be a poten- sequential anthracycline/taxane regimen. tially valuable regimen in stage I elderly patients or in elderly In addition to these studies favouring weekly paclitaxel, relevant patients not considered candidates for polychemotherapy. data come from Barcenas et al. who used the SEER/Texas Cancer Registry-Medicare database to compare the risk of hospitalization in patients with early-stage BC who received different chemother- Discussion and recommendations apy regimens [70]. Among patients older than 65 years, AC and TAC (but not dose-dense AC plus paclitaxel) were associated with a Although BC is the leading cause of cancer death in women, higher risk of hospitalization than TC. although risk of the disease increases with age, and although the Following promising results with nab-paclitaxel in MBC, the ICE proportion of the population over 65 years of age is rapidly II study compared investigators’ choice of epirubicin plus expanding, few randomized controlled trials (RCTs) have systemat- cyclophosphamide or CMF versus weekly nab-paclitaxel plus cape- ically investigated treatment options in older BC patients; and citabine in 400 non-frail elderly patients at increased risk of older women are substantially under-represented in registration relapse [71]. Although not the primary endpoint of the trial (which studies. 24 L. Biganzoli et al. / Cancer Treatment Reviews 43 (2016) 19–26

Table 1 SIOG Task-force recommendations on the use of taxanes in elderly breast cancer according to setting and tumour biology.

Setting Regimen Evidence in the Recommendation elderly Adjuvant HER2-negative A/E-based (3–4 cycles) ? Sub-group analyses Only ﬁt and high-risk patients; caution about cardiotoxicity and taxane (3–4 cycles) haematotoxicity; primary prophylactic G-CSF for anthracycline part (and docetaxel 3 weekly if that taxane is chosen) AC/EC Â 4 Prospective studies Feasible in the standard elderly population with caution about cardiotoxicity; primary prophylactic G-CSF CMF Â 6 Prospective studies Feasible in the standard elderly population with caution about haematotoxicity and compliance TC Â 4 Sub-group analyses Feasible in the standard elderly population with primary prophylactic G-CSF Weekly docetaxel Prospective study Not recommended Weekly paclitaxel No evidence But may be considered in patients who are not candidates for poly-chemotherapy such as TC Nab-paclitaxel plus capecitabine Prospective study Not recommended HER2-positive A/E-based (3–4 cycles) ? Sub-group analyses Only ﬁt and high-risk patients; caution about cardiotoxicity and taxane (3–4 cycles) + trastuzumab haematotoxicity; primary prophylactic G-CSF for anthracycline part (and docetaxel 3 weekly if that taxane is chosen) TCH (C = carboplatin) Â 6 No Concern about toxicity TC Â 4 + trastuzumab No Feasible in the standard elderly population with primary prophylactic G-CSF, especially in presence of risk factors for cardiotoxicity Weekly paclitaxel (3 months) + No evidence But may be considered in elderly patients who are not candidates trastuzumab for poly-chemotherapy such as TC Metastatic Weekly paclitaxel Prospective study Feasible Docetaxel q3w Sub-group analyses Feasible Consider primary prophylactic G-CSF* Weekly docetaxel Prospective study Feasible Nab-paclitaxel Sub-group analyses Feasible

A = doxorubicin, E = epirubicin, C = cyclophosphamide, G-CSF = Granulocyte Colony Stimulating Factor, M = methotrexate, F = 5-ﬂuorouracil, T = docetaxel, H = trastuzumab. * EORTC guidelines for the palliative setting recommend using G-CSF only if there are no similarly effective regimens not requiring G-CSF.

Level I evidence is therefore lacking. In its absence, recommen- at symposia of Amgen, Bayer Schering, Cephalon, Chugai, GSK, Hel- dations are based in part on trial evidence that does not achieve sinn, Hospra, Ipsen, JnJ OrthoBiotech, Merck, Merck Serono, Novar- the standard of RCTs, on extrapolation from controlled trials in tis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Teva, Vifor. which elderly patients are poorly represented, on subgroup analy- Sibylle Loibl declared no conflict of interest. ses and on clinical experience. HW has received lecture fees, consulting fees and scientific Haematological toxicity may be circumvented by the use of grants that have only been used for scientific purposes, from the weekly schedules. However peripheral neuropathy remains an following: Amgen, Roche, MMS Belgium, Pfizer US Commercial important issue irrespective of schedule, reaching up to 40% Operation, Novartis Pharma, Teva Pharmaceuticals Europe, Celgene grade P 2 in the general population. A careful assessment of func- International, Baxter Belgium. tionality should be performed, based on the last SIOG update on Etienne Brain declared no conflict of interest. CGA [7]. Discussing the cost and cost-effectiveness of different therapies Acknowledgements is difficult since drug prices vary considerably according to healthcare system, and, even within a single country, may differ Rob Stepney, medical writer (Charlbury, UK), prepared the first from one hospital or insurance provider to another. Within the draft of this paper and edited subsequent drafts. Dr Stepney has limits of the health-economic methodologies used, and accepting declared that the only remuneration received was from SIOG and that healthcare systems differ by country, it has been calculated that he has no conflicts of interest. We also acknowledge the help- that nab-paclitaxel is a cost-effective alternative to standard tax- ful comments of the SIOG internal review panel: Evandro de Azam- anes when the balance between efficacy and the expense of dealing buja, Martine Extermann, Gilbert Zulian, Miguel Martin, with foreseeable toxicities is taken into account [79–82]. Alessandro Minisini and Jonas Bergh. With these caveats, we propose as a summary of the current position the statements shown in Table 1. References

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