Cognitive Decline and Adjuvant Breast Cancer Chemotherapy: A Matter of Dose?
Abstract & Commentary
By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: Breast cancer patients who received either high-dose, standard-dose or no chemotherapy were studied prospectively, utilizing a comprehensive battery of neuropsych tests. Compared to controls, only the group receiving the high-dose treatment experienced a deterioration in cognitive function.
Source: Schagen SB, et al. Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst. 2006;98:1742-1745.
For some, survival after cancer chemotherapy has been associated with a noted decline in cognitive function. Prior cross-sectional studies have supported the notion that chemotherapy may influence brain function in some patients.1-3 In the current report from The Netherlands, a prospective analysis was performed. For this, two groups of breast cancer patients were randomized to receive either high-dose or standard-dose adjuvant chemotherapy and their cognitive function before and after therapy was assessed. A third group of breast cancer patients who received no chemotherapy and a group of women without breast cancer were similarly studied. The latter two groups had cognitive assessments at a predefined interval of either 12 months (breast cancer no chemotherapy) or 6 months (control group). The neuropsychological testing consisted of ten tests comprising 24 test indices covering a wide range of cognitive domains.
The chemotherapy-treated patients were those who were considered high risk for recurrence. They were randomly assigned to receive either standard dose chemotherapy comprised of five monthly cycles of 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2) and cyclophosphamide (500 mg/m2) followed by radiotherapy and tamoxifen (40 mg daily for 2-5 years) (FEC group; n = 39), or high-dose chemotherapy (four cycles of FEC, as above followed by one cycle of cyclophosphamide 6 gm/m2, thiotepa 400 mg/m2 and carboplatin 1.6 g/m2 (CTC group; n = 28). There were 57 patients in the breast cancer/no chemotherapy group (no CT) and 60 women in the no breast cancer-control group.
At the first assessment, there were no detected differences among the four groups. However, more of the women treated in the CTC (high-dose) group experienced a decline in cognitive function over time than the control group (25% vs 6.7%; odds ratio [OR] = 5.3; 95% confidence interval [CI] = 1.3-21.2; P = 0.02). No such difference was observed for the FEC or the noCT groups (FEC vs control: OR = 2.2; 95% CI = 0.5-9.1; P = 0.27; noCT vs control: OR = 2.2; 95% CI = 0.6-8.0; P = 0.21). Repeated measures multiple analysis of covariance showed that deterioration in cognitive performance over time occurred across a variety of tests that measured cognitive functions. However, the measures that were sensitive to the so-called "executive function" exhibited the strongest effects.
Commentary
The concept that chemotherapy may negatively influence higher brain function is well appreciated but neither the degree to which it occurs nor the population's most susceptible have been clearly established. The current report provides some important clues. The two different treatment groups were randomly assigned and, although the two additional control groups were quite different in several ways, there was no difference among the groups at the initial cognitive assessment. Only the group that received the high-dose regimen had a measurable deterioration. Those receiving standard-dose chemotherapy were no different than controls. This raises the possibility that either the specific drugs (thiotepa-tepa, etoposide and carboplatin) used in the high-dose group, or the actual dose intensity (eg, cyclophosphamide at 6 gm/m2) resulted in impaired cognitive function. It would seem the latter is most likely. Yet, not all patients in the high-dose group had a measurable decline and it remains unclear which patients are vulnerable for this adverse outcome.
Thus, this well-constructed analysis provides prospective data confirming the findings of the earlier cross-sectional studies. Hopefully, future studies will identify those drugs, combinations or doses that are most dangerous in this regard and/or those constitutional features of some, but not all, cancer patients that make them particularly susceptible.
References
1. Van Dam FS, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst. 1998;90:210-218.
2. Ahles TA, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol. 2002;20:485-493.
3. Brezden CB, et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol. 2000;18:2695-2701.
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