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
] – is being challenged [11
]. 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
]. 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
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
], 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.
While the present analysis has provided a wealth of important new data, it is important to acknowledge its limitations – namely, the post hoc nature of the analysis, a relative paucity of patients aged > 70 years, the probability that the patient population is not representative of older patients as a whole due to general exclusion of patients with comorbidities from clinical trials, and the lack of any exact prognostic score such as the Charlson score for enrolled older patients. Heterogeneous use of growth factors between the studies analyzed and their chemotherapy regimens may also have had an impact on some of the variables assessed.
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
]; 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
]. 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.