Different adjuvant chemotherapy regimens in older breast cancer patients?

Content Provider	Semantic Scholar
Author	Wildiers, Hans Brain, Etienne G. C.
Copyright Year	2015
Abstract	Adjuvant chemotherapy for early breast cancer patients improves survival in general, but estimating true benefit on the individual level remains a challenge, especially for older individuals. There are some data suggesting that older individuals, certainly those at higher risk of relapse, can indeed derive benefit from adjuvant chemotherapy, and this therapy should certainly not be denied on the basis of age alone, if only to ensure equal access to health care [1, 2]. There are many studies showing provocatively much lower use of adjuvant chemotherapy in older people probably because of fear for toxicity and futile treatment [1, 2], but also very likely, although poorly reported, because goals in life shift throughout the course of lifetime from mere quantity of life to more quality of life. Older patients more often die of other causes than breast cancer and treatment side-effects can seriously affect quality of life. However, let us not forget that elderly breast cancer patients also die more often of breast cancer [3], demonstrating that undertreatment, the other extreme position mirroring overtreatment, can negatively affect outcome. If the decision to administer adjuvant chemotherapy is made for an individual old person, the next question is the choice of the regimen. Unfortunately, most frequently used regimens have been studied in younger fit populations. Some studies have included a proportion of patients above age 70, but actually rather a selection of fitter elderly, not representative of the general population, while previous studies [4] have even debarred those above age 70 from participation. There are many reports showing higher toxicity with standard adjuvant chemotherapy regimens when age increases [1, 2]. Hospitalization rate is also clearly higher in the elderly [5]. In the adult population, the classical CMF regimen (cyclophosphamide, methotrexate, fluorouracil) has largely and progressively been replaced by anthracyclines-based regimens, and later by sequential or combined anthracyclineand taxane-based regimens, because of improved efficacy [1]. However, the use of anthracyclines remains a sensitive matter because of the risk of cardiac failure, whose incidence increases with age [6]. Moreover, we are unaware of any solid evidence-based validation of sequential regimens in elderly, even when avoiding the approved ‘high dose’ of docetaxel (100 mg/m2) or the triplet TAC (docetaxel, doxorubicin, cyclophosphamide) combination [7], both highly myelosuppressive, especially in elderly for whom baseline neutrophil counts are often misleading to estimate bone marrow functional reserve. For all these reasons, there is a tendency to bypass these standard regimens developed in younger adults when treating elderly patients, referring to empirically adjusted ones especially in those patients who are not 100% fit and who represent the most important segment of the elderly population. Few attempts have been done to develop elderly specific strategies. The ELDA trial published in this journal [8] is such an example. The study randomized 302 women aged 65–79 years, operated for breast cancer, with average to high risk of recurrence, to CMF or weekly docetaxel for 4–6 cycles according to hormone-receptor status. In contrast to the assumption, docetaxel did not improve outcome compared with CMF [HR for disease-free survival (DFS) 1.21; P = 0.32]. Haematological toxicity was less pronounced for docetaxel, but non-haematological toxicity and quality of life were conversely significantly worse: of note, two cases of intestinal necrosis events yielding 1.36% toxic death rate certainly do not match the definition of ‘soft chemotherapy’. However, the authors are to be congratulated for performing and finishing a randomized trial in the older population. Several trials in the past (CASA trial, ACTION trial) have failed to do this, supposedly because of the difficulty to convince elderly for trial participation [9] which actually may be an emotional interpretation rather than a fair and objective one. Only one large adjuvant trial in this population has been published recently [10], showing that a ‘soft’ oral adjuvant chemotherapy regimen with capecitabine is clearly inferior to standard chemotherapy, CMF or AC (adriamycin, cyclophosphamide). How should we interpret the results of the ELDA trial in this context? First, it must be acknowledged that both arms (CMF or docetaxel weekly) are not standard adjuvant regimens. Weekly docetaxel has not been previously studied as ‘monotherapy’, and when used after anthracyclines, it is clearly more toxic than weekly paclitaxel in the general population [11]; CMF is generally considered inferior to regimens combining anthracyclines and taxanes, as mentioned before. Taken together with the observed toxicity in the ELDA trial, this does not encourage the use of either regimen in the older population despite the lack of direct comparisons with less fuddy–duddy regimens. Because of this poor situation, we end up selecting regimens studied in the general population that are potentially and safely usable in the elderly. Sequential regimens like AC followed by weekly paclitaxel are certainly feasible, but only in fit older patients, not forgetting that age remains a clear risk factor for anthracycline-related cardiotoxicity. Although attractive, weekly paclitaxel monotherapy in the general (not high-risk) population [12] did not achieve noninferiority compared with AC (HR for relapse free survival 1.26), so cannot be recommended. The TC (docetaxel cyclophosphamide) regimen [13] is an attractive option for elderly since it was superior to AC for DFS and overall survival (OS) irrespective of ed ito ria ls editorials Annals of Oncology 26: 613–615, 2015 doi:10.1093/annonc/mdv015 Published online 18 January 2015
Starting Page	722
Ending Page	733
Page Count	12
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PubMed reference number	25600566v1
Alternate Webpage(s)	https://doi.org/10.1093/annonc/mdv015
DOI	10.1093/annonc/mdv015
Journal	Annals of oncology : official journal of the European Society for Medical Oncology
Volume Number	26
Issue Number	4
Language	English
Access Restriction	Open
Subject Keyword	Adjuvant Study Adverse reaction to drug Alveolar rhabdomyosarcoma Anthracyclines Bone Marrow Cardiotoxicity Cessation of life Chemotherapy Regimen Chemotherapy, Adjuvant Cyclophosphamide Daclizumab Doxorubicin Editorial Estimated Fluorouracil Heart failure Hematological Disease Intestinal necrosis Mammary Neoplasms Methotrexate Overall Survival Paclitaxel Patients Pharmaceutical Adjuvants Radioimmunoassay Scientific Publication TAC Regimen Taxanes benzoyl-coenzyme A taxane 2-O-benzoyltransferase bypass capecitabine cyclophosphamide/fluorouracil/methotrexate protocol docetaxel neutrophil
Content Type	Text
Resource Type	Article