Clinical feasibility of (neo)adjuvant taxane-based chemotherapy in older patients: analysis of >4,500 patients from four German randomized breast cancer trials

The incidence of breast cancer in women aged 65 years and older is the highest in all age groups. These older patients are generally underrepresented or even excluded from clinical trials, however, leading to a gap in data about the compliance, safety, and efficacy of highly active taxane-based treatments in older patients. From several clinical trials, there is a growing awareness that older primary breast cancer patients achieve significant survival benefits with (neo)adjuvant chemotherapy regimens. Regarding the steady increase of life expectancy today, this should be considered in treatment of older patients in clinical routine.

There is evidence in breast cancer that the use of taxanes in adjuvant chemotherapy yields a survival benefit – especially from the PACS 01 study, demonstrating a particular benefit in women aged 50 years or older [1]. There are relatively few data, however, on the use of these agents in older patients [2]. Owing to concerns about tolerability, there remains a tendency in clinical routine to use less dose-intensive chemotherapy in older patients with the avoidance of those agents perceived to be more toxic. We therefore combined data of different adjuvant and neoadjuvant trials with taxane-containing regimens. Here we present the results of the first systematic pooled analysis of tolerability data for taxane-based regimens in older primary breast cancer patients.

A pooled analysis of four German prospective, randomized clinical trials, conducted during 1999 to 2005, was performed. These trials included primary breast cancer patients receiving taxane-containing neoadjuvant or adjuvant chemotherapy. The meta-database was closed in October 2006; the number of patients in the present analysis may therefore differ from the separate study publications. For every study, however, the number of patients included in the present analysis exceeds 75% of those evaluable. Toxicity data from the studies were analyzed for taxane-containing chemotherapy in older patients (aged > 64 years) compared with toxicity data from patients aged < 60 years and those aged 60 to 64 years treated in the same studies. The treatment regimens of the four trials included are depicted in Figure 1.

In the ADEBAR trial (NCT00047099), patients (n = 1,106/1,502) received four cycles of adjuvant chemotherapy either with epirubicin/cyclophosphamide every 3 weeks followed by four cycles of docetaxel every 3 weeks, or six cycles of 5-fluorouracil, epirubicin on days 1 and 8 and cyclophosphamide on days 1 to 14 every 4 weeks [3].

In the ASG 1–3 trial (NCT00668616), patients (n = 772) received four cycles of adjuvant chemotherapy either with epirubicin/cyclophosphamide every 3 weeks then four cycles of paclitaxel every 3 weeks, or with four cycles of epirubicin every 2 weeks and then four cycles of paclitaxel every 2 weeks (unpublished data, Kümmel S. et al).

In the GeparDuo trial (NCT00543829), patients (n = 902) received four cycles of neoadjuvant chemotherapy with doxorubicin/cyclophosphamide every 3 weeks followed by four cycles of docetaxel every 3 weeks or four cycles of doxorubicin/docetaxel every 2 weeks [4].

In the GeparTrio trial (NCT00544765), patients (n = 1,988/2,072) received two cycles of neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC) followed by either four cycles of TAC or six cycles of TAC or four cycles of vinorelbine plus capecitabine every 3 weeks [5, 6].

For the purpose of the analysis, chemotherapy regimens were divided into four chemotherapy schedules: combination taxane schedule, TAC 75/50/600 mg/m²; sequence schedule, doxorubicin(epirubicin)cyclophosphamide 60(90)/600 mg/m² followed by docetaxel 100 mg/m² or paclitaxel 175 mg/m²; combination dose-dense schedule, dose-dense doxorubicin/docetaxel 50/75 mg/m²; and sequence dose-dense schedule, dose-dense epirubicin/dose-dense paclitaxel 120/175 mg/m².

Across the four studies, 422 patients aged ≥ 65 years (out of 4,227 patients), with a median age of 67 years (range 65 to 80 years), received 1,674 cycles of taxane-containing chemotherapy regimens. Furthermore, 3,160 patients aged < 60 years, with a median age of 47 years (range 23 to 59 years), received 14,146 cycles of taxane-containing chemotherapy regimens. Across the studies, 2,674 cycles were given to patients aged between 60 and 64 years. Demographic and clinical characteristics of the patients who received a taxane-containing chemotherapy and the summary data for all 'older' patients (aged > 64 years and aged 61 to 64 years) and 'younger' patients (aged < 60 years) are presented in Table 1.

There is a growing awareness that age per se is a less important determinant of choice of therapy concepts and outcome in older cancer patients than physical status, functional status, and mental/emotional status. Indeed, it is becoming more and more evident that older, but otherwise healthy, patients with primary breast cancer can accrue the same benefits from standard chemotherapy as younger patients – especially when regarding the steady increase in life expectancy and quality of life in western societies. The clinical assumption that most older patients are too frail to receive standard chemotherapy – reflected in, for example, less use of adjuvant chemotherapy in older breast cancer patients [8‐10] – is being challenged [11, 12]. There is a paucity of published data from chemotherapy trials comparing older with younger cancer patients, however, which has hampered efforts to improve treatment strategies for this population. This lack of data arises from the common underrepresentation, if not routine exclusion, of older patients from many clinical trials [13‐15]. Additionally, there are pharmacokinetic data demonstrating that both taxanes can be used in older patients without dose modifications but in the case of an impaired liver function neither paclitaxel nor docetaxel should be applied due to their high liver metabolization [16‐18].

The present analysis constitutes the largest pooled analysis to date of the use of taxanes in older patients with primary breast cancer. The incidences of dose delays, dose reductions, treatment discontinuations, and hospitalizations all increased with age. With regard to taxane therapy, the combination dose-dense doxorubicin/docetaxel schedule was the most problematic overall, with a particularly high incidence of hospitalizations compared with other schedules. One cannot conclude, however, that nontaxane therapies are the preferred option. In a previous analysis of the data, the regimen of 5-fluorouracil, epirubicin on days 1 and 8 and cyclophosphamide on days 1 to 14 [19] was by far the most toxic regimen overall [20].

Amongst the taxane schedules, TAC was overall associated with the highest incidence of toxicity. In our analysis, paclitaxel had significantly less hematologic toxicity compared with docetaxel – which is consistent with data from a prospective adjuvant trial directly comparing those taxanes [21]. Moreover, in an adjuvant anthracycline/taxane sequential regimen, weekly paclitaxel shows the same efficacy as docetaxel [21]. This might therefore be the preferred taxane regimen, at least for older patients. The relatively low incidence of hematologic toxicity, with the exception of low-grade anemia, with the sequence dose-dense schedule is notable and may reflect the sequential dosing schedule and the obligatory use of granulocyte-colony stimulating factor therapy.

With regard to higher grade nonhematologic toxicity, mucositis, loss of appetite, infection with neutropenia, and fatigue were more common with increasing age. In patients treated with docetaxel, skin changes of grade 3 to grade 4 increased with age.

Analysis of the data by age shows that there was generally a higher incidence of dose delays/reductions, hospitalizations and therapy discontinuations, of hematologic toxicity, and of some nonhematologic toxicity such as loss of appetite and grade 3 to grade 4 fatigue and mucositis in 'older' versus younger patients. One might argue that such an age split in three different groups is artificial, that a higher age should be considered to constitute 'older' patients, and that simple discrimination by age alone does not account for other factors (such as physical status). Nevertheless, these data provide an important insight into the acceptable tolerability of chemotherapy in older patients with primary breast cancer and could be confirmed by data from patients with ovarian cancer [13].

The patient cohort for the four trials analyzed reflects clinical trial routine at that time and substantiates findings from other studies [22‐24], demonstrating that – even if the trials had no upper age limit – older patients were generally included less frequently or not included. This may have changed since the data published by Muss and colleagues [25], which showed that the benefit from chemotherapy did not differ across age groups although treatment-related mortality was higher (1.5% versus 0.42%) in the group aged > 65 years.

In summary, our analysis indicates that – with pretreatment older assessment and appropriate supportive care such as granulocyte-colony stimulating factor therapy for neutropenia prophylaxis – older patients can be considered for taxane therapy and the maintenance of dose intensity should be feasible. Older patients generally have an increased susceptibility for myelotoxicity [26‐28]; this has recently been acknowledged by the updated EORTC guidelines, which recommend general use of granulocyte-colony stimulating factor prophylaxis if the risk of FN is ≥ 20% and risk-adapted use in cases where the FN risk is between 10% and 20% [26]. Our findings are in accordance with other studies that have, for example, suggested docetaxel therapy as a viable treatment option in older cancer patients [29, 30]. In particular, sequential therapy should be preferred among older patients. It has therefore become increasingly clear that (neo)adjuvant therapy concepts for older patients should consider – next to oncological needs – the patient's physical and functional status, and should not be determined merely on the basis of their age as in the ICE trial of the German Breast Group. Otherwise older patients will continue to be undertreated and will not benefit from the advances in medicine.

The pooled analysis of a substantial cohort of older primary breast cancer patients demonstrates that taxane-containing (neo)adjuvant chemotherapy is feasible in older patients and that toxicity can be reduced by sequential therapy regimens and consequent use of prophylactic treatment.