A Prospective Pharmacologic Evaluation of Age-Related Toxicity of Adjuvant Chemotherapy in Women with Breast Cancer

Abstract

Despite increasing evidence of benefit from adjuvant chemotherapy, older women with breast cancer are commonly given less aggressive treatment than younger patients. Conflicting prior data regarding age-related toxicity prompted this prospective study. Forty-four women (aged 35-79 years) with early-stage breast cancer were treated with four cycles of adjuvant therapy with doxorubicin 60 mg/m2 i.v. and cyclophosphamide 600 mg/m2 i.v. every 21 days. They were monitored for myelosuppression, cardiotoxicity, and decrease in quality of life. Pharmacokinetics were analyzed using cycle 1 plasma samples. Bone marrow granulocyte and macrophage colony-forming units (CFU-GM) were assayed in vitro for dose response to 4-hydroperoxycyclophosphamide and doxorubicin before cycle 1. There was moderate evidence of age-related decrease in nadir absolute neutrophil count (ANC) when age was viewed as a continuous variable. On average there was a 10/microliter drop in cycle 1 nadir ANC for every year increase in age (p = 0.02). However, when age was viewed as a categorical variable (age < 65 vs. > or = 65 years), a similar proportion of women in each group reached an ANC < 100 (18% vs. 19%). Neither neutropenic complications, alteration in cardiac function, nor change in quality of life scores were significantly age related (p > 0.12). Pharmacokinetic analyses did not demonstrate age-related differences in the clearance of either doxorubicin or cyclophosphamide (p > 0.8). Pharmacodynamic analysis of individual patient bone marrow progenitor cell sensitivity did not reveal any correlation with age (p > 0.48). In women undergoing adjuvant therapy for breast cancer, no clinically significant age-related trends in toxicity were observed. These data suggest that older age alone should not exclude patients from receiving adjuvant therapy with doxorubicin and cyclophosphamide.

Diagnosis and Treatment of Breast Cancer in the Elderly

“…A comparable incidence of side effects including myelosuppression, cardiotoxicity, and a decrease in quality of life in relatively healthy women over 65 has recently been reported by Dees, et al using the common adjuvant regimen, doxorubicin and cyclophosphamide. 59 Crivellari, et al 56 have evaluated the toxicity of a standard adjuvant therapy regimen, CMF (cyclophosphamide, methotrexate and fluorouracil), in older patients. Important side effects of CMF including Grade 2 and 3 mucosal toxicity (diarrhea, gastritis, and mucositis) and hematologic toxicity were increased in patients older than 65 years.…”

Optimal management of the elderly patient with head and neck cancer: Issues regarding surgery, irradiation and chemotherapy

“…The ongoing debate: A number of retrospective studies in various solid tumors have reported that toxicity in general is not increased in the elderly [49][50][51] , although these results have been challenged by other studies [52][53][54] . In elderly patients with advanced HNC in particular, combined data from two phase Ⅲ randomized trials [43] , conducted by the Eastern Cooperative…”

Does chemotherapy-induced neutropaenia result in a postponement of adjuvant or neoadjuvant regimens in breast cancer patients? Results of a retrospective analysis

“…This standard could be debatable according to recent results of randomised trials showing a significant reduction in breast cancer recurrence and mortality with adjuvant chemotherapy for elderly patients (Fargeot et al, 2004;Muss et al, 2005). On the other hand, the advanced age has been found to be an independent prognostic factor of decrease in RDI (Bonadonna et al, 1995;Crivellari et al, 2000;Lyman et al, 2003;Shayne et al, 2006), and to be associated with a higher rate of neutropaenic complications (Crivellari et al, 2000;Dees et al, 2000;Muss et al, 2007), of which clinical consequences were more severe (Balducci and Yates, 2000). Second, the 3 FEC100-3D regimen may be a favourable schedule for re-treatment with a low ANC as docetaxel (D) induces deep but short neutropaenia always corrected on day 22.…”