Cognitive Decline from Adjuvant Chemotherapy for Breast Cancer?
Cognitive Decline from Adjuvant Chemotherapy for Breast Cancer?
ABSTRACT & COMMENTARY
Three groups of patients were entered, all younger than 55 years: a control group with stage I breast cancer who received no adjuvant therapy (34 patients) and two groups of patients with high-risk breast cancer defined as stage II or III disease with four or more positive axillary nodes, one of which received four cycles of FEC combination chemotherapy (5-fluorouracil 500 mg/m2, epirubicin 90-120 mg/m2, cyclophosphamide 500 mg/m2) followed by locoregional radiation therapy (34 patients) and the other, which received the same chemotherapy followed by a fifth course of CTC chemotherapy (cyclophosphamide 6 gm/m2, thiotepa 480 mg/m2, carboplatin 1.6 gm/m2) with autologous hematopoietic stem cell transplantation, then by locoregional radiation therapy (36 patients). In both chemotherapy arms, patients received tamoxifen 40 mg/day for two years.
Patients were assessed a minimum of six months after completion of hormonal therapy. Cognitive impairment was detected in 9% of patients who received no adjuvant therapy. Seventeen percent of those receiving conventional-dose chemotherapy plus radiation therapy plus hormonal therapy showed abnormal cognitive function, and 32% of those undergoing the same therapy plus a course of high-dose therapy had cognitive impairment. Expressed in terms of risk, those receiving high-dose therapy had an 8.2-fold increased risk of abnormal performance on the cognitive tests compared to controls; those receiving conventional dose therapy had 3.5 times the risk of controls. When the checklist for cognitive problems in daily life was applied, about one-third of patients receiving treatment reported alterations in concentration, 30% had memory problems, 16% had thinking difficulties, and 11% had language problems.
No differences were noted between the two chemotherapy groups but both groups had significantly more cognitive difficulties than the control group. It is not clear whether the level of difficulty they experienced actually interfered with their normal functioning. With regard to quality-of-life questionnaires, some decline in level of function was noted in individual function scales in patients treated with high-dose therapy; however, no differences were noted using the global quality-of-life scale. The only symptom that was more common in the treatment arms was fatigue among those receiving high-dose therapy. Depression was also seen more commonly in those receiving high-dose therapy than in those receiving conventional dose or no adjuvant therapy. Anxiety was equally prevalent among the groups. (van Dam FSAM, et al. J Natl Cancer Inst 1998;90:210-218.)
COMMENTARY
The pediatric oncology community has done a better job of assessing the effect of cancer treatments on subsequent health events in children than has the adult oncology community for their adult patients. Of course, many curable childhood cancers have a predilection to involve the central nervous system (e.g., acute leukemia), and the therapy can be said to be designed to penetrate the brain. Some effort has been made to evaluate the influence of systemic chemotherapy and cranial irradiation on cognitive function in survivors of acute lymphoblastic leukemia.1 Girls who received high-dose methotrexate plus cranial irradiation experienced a nine-point decline in intelligence quotient (IQ); boys receiving the same treatment were not significantly affected. A generalized decline in verbal memory was noted that was independent of the use of cranial irradiation; the implication is that an agent involved in leukemia treatment, perhaps the glucocorticoid,2 is a neurotoxin.In adult patients, those few long-term survivors with small cell lung cancer have been noted to experience cognitive decline, and prophylactic cranial irradiation has been implicated. However, the only systematic study of such patients noted that nearly all the patients had cognitive dysfunction following the systemic chemotherapy and chest radiation therapy before cranial irradiation was delivered.3 Although systemically administered chemotherapeutic agents penetrate the blood-brain barrier poorly or not at all and radiation delivered to fields outside of the brain cannot damage the brain directly, both chemotherapy and chest radiation therapy deliver substantial free radicals to the blood. Hemoglobin-bound oxygen has been shown capable of generating superoxide.4 Thus, it is possible that chemotherapy and radiation effects on the blood could be the mediators of central nervous system toxicity as the red blood cells deliver more than oxygen to the brain.
This report from the Netherlands is important for several reasons. First, and most obviously, the results affect a large number of women. Second, the inclusion of an untreated control group adds power to the conclusions. Third, it suggests a relationship between depression and decreased cognition. Finally, the results suggest a dose-response effect where more intensive therapy elicits greater deficits. Given the general trend to try to improve cancer outcomes with more intensive adjuvant treatments, these results place an additional constraint on the ongoing work. It would seem desirable to develop a better understanding of the basis of these detrimental effects on cognitive function and to test methods of preventing them. In addition, agents such as estrogen, non-steroidal antiinflammatory agents, selegiline, vitamin E, tacrine, and donepezil are said to influence cognitive function in other disease states, most notably Alzheimer’s disease. Until the mechanism of the damage in cancer patients is understood, these and other agents should be tested empirically for their ability to exert a beneficial effect on cognitive function in patients undergoing adjuvant therapy.
The study does have several flaws, however. The number of patients is small. Twenty-two percent of patients eligible for the study refused to participate, a fraction large enough to influence the outcome if they are not representative of the group as a whole. The relationship between the degree of cognitive decline and functional interference with performance cannot be discerned from the data. It would be useful to know whether any women had difficulty with the day-to-day tasks of living or had difficulty resuming their jobs. Another concern is its cross-sectional design. Cognitive function is more meaningfully studied longitudinally.
Nevertheless, this paper is destined to be considered a hallmark in oncology. It marks the beginning for the addition of cognitive end points to adjuvant chemotherapy and radiation therapy studies. It defines a new area of clinical investigation. It introduces yet another long-term side effect of therapy that becomes an issue as larger numbers of patients survive for many years after a diagnosis of cancer.
References
1. Waber DP, et al. J Clin Oncol 1995;13:2490.2. McIntosh LJ, Sapolsky RM. Exp Neurol 1996;141:201.
3. Komaki R, et al. Int J Radiat Oncol Biol Phys 1995;33:179.
4. Balagopalakrishna C, et al. Biochemistry 1996;35:6393.
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