Breast cancer remains the most
common cancer diagnosed in
women, with 192,200 new cases expected in 2001. Breast cancer mortality has
slowly but significantly declined over the past 5 years due to improved
widespread mammographic screening coupled with the initiation of adjuvant
systemic therapies. Over the past decade, chemohormonal therapy has assumed
extensive acceptance in the adjuvant treatment setting for both lymph node-positive
and -negative breast cancer. As patients with earlier-stage breast cancer
derive an enhanced mortality benefit from adjuvant therapy, they may also
unfortunately incur several short- and long-term side effects from both
chemotherapy and hormonal therapy. As the ranks of truly long-term breast cancer
survivorship increase, further attention must be directed toward several
An underinvestigated area of oncologic care involves the
documentation and analysis of possible impairment of cognitive function in
patients treated with various oncologic drugs. Many anecdotal reports have been
made by patients with malignancies who have received chemotherapy. These
patients have reported disturbing and disruptive changes in their memory,
attention span, ability to concentrate, and language skills.[3,4]
Despite the relative frequency of patient reports of cognitive
dysfunction, few studies have analytically documented the degree of
neuropsychological impairment through standardized testing methods. Studies that
have been performed have lacked sufficient patient numbers, included mostly
pediatric patients, or have centered on either adult oncologic patients with
advanced metastatic disease or those treated with high-dose chemotherapy
followed by transplantation.[6,7] In addition, past attempts to document
neuropsychological impairment have relied solely upon patient quality-of-life
assessment tools that lack true quantification and may intertwine diminished
cognitive function with anxiety and depression.
Over the past 6 years, four studies have assessed the
neuropsychological sequelae of adjuvant chemohormonal therapy in women with
breast cancer. This includes work by Wieneke and Dienst in 1995, van Dam et
al in 1998, Schagen et al in 1999, and Brezden et al in 2000.
Wieneke and Dienst studied the cognitive function of a small
cohort of previously healthy, relatively young, and well-educated women with
early-stage breast cancer following standard-dose adjuvant chemotherapy. A total
of 28 patients, ranging in age from 28 to 54 years, were enrolled. Adjuvant
chemotherapy regimens included 17 patients treated with CMF (cyclophosphamide
[Cytoxan, Neosar], methotrexate, fluorouracil [5-FU]); 7 patients treated with
CMF followed by CAF (cyclophosphamide, doxorubicin [Adriamycin], 5-FU); and 4
patients treated with CAF. Duration of chemotherapy was variable, ranging from 3
to 18 months, with the average course lasting 6.7 ± 3 months.
Patients underwent a comprehensive battery of neuropsychological
tests to assess eight domains of cognitive function. Depression was assessed
using the Beck Depression Inventory (BDI). While all patients underwent the same
lengthy neuropsychological evaluation following completion of chemotherapy, two
additional variables were introduced: (1) More than one-third of patients were
taking adjuvant tamoxifen (Nolvadex) at the time of testing, and (2) patients
had discontinued chemotherapy an average of 6.6 ± 4 months prior to the time of
testing, with a range of 0.5 to 12 months.
Results: When compared with published test norms of
otherwise healthy age- and educationally matched controls, a significant
decrease in the study participants’ cognitive function was observed. Of the
adjuvantly treated patients, 75% showed mild-to-moderate clinical impairment in
five of the cognitive domains tested, including attention/concentration, memory,
mental flexibility, motor function, and visuospatial ability. Only the domains
of abstract reasoning and verbal fluency appeared intact when compared with
published test norms. Of all the analyzed treatment variables, only duration of
chemotherapy was significantly related to the degree of cognitive impairment. Of
the study participants, approximately 80% showed minimal or no evidence of
depression, and no significant relationship was found between the BDI and
neuropsychological test scores.
Study Limitations: Criticisms of this study include the
different adjuvant chemotherapy regimens used, variable durations of
chemotherapy administration, variable timing of neuropsychological testing
following the completion of chemotherapy, introduction of adjuvant tamoxifen in
a small percentage of patients, overall small study size, and possible patient
recruitment bias. Perhaps the two most important criticisms of this study
involved the use of previously published test norms of healthy individuals as
controls coupled with the failure to establish a baseline for the
participants’ pretreatment cognitive functioning.
Oncologic patients probably differ significantly from the
typical disease-free normative population, which may lead to an overestimation
of differences. In evaluating the neuropsychological function of patients with
limited-stage small-cell lung cancer treated with combined-modality therapy via
a large Cancer and Leukemia Group B trial, Ahles et al compared the pretreatment
baseline of cognitive function with age-matched published norms. Prior to
receiving any chemotherapy or radiation therapy, these patients with lung cancer
performed in the lowest quartile, compared to otherwise healthy controls (ie,
three-fourths of people in this age range scored better than patients in the
trial). Thus, cognitive functioning in selected oncologic patients may not be in
the normal rangeeven before any treatment has occurred.
FIRST DUTCH STUDY
Two recent Dutch studies have documented clinically significant
cognitive dysfunction in women receiving adjuvant chemohormonal therapy for
breast cancer. In the first study, by van Dam et al, 83 patients less than
55 years of age with high-risk breast cancer were randomized to receive
standard-dose chemotherapy vs high-dose marrow-ablative chemotherapy with
autologous stem cell support. Study participants had either stage II or III
breast cancer with four or more positive axillary lymph nodes by surgical
Standard-dose chemotherapy consisted of four cycles of FEC
(5-FU, 500 mg/m2 IV; epirubicin [Ellence], 90 to 120 mg/m2 IV;
cyclophosphamide, 500 mg/m2 IV). High-dose chemotherapy included four cycles of
standard-dose FEC followed by a fifth cycle of dose-intensified
cyclophosphamide, 6 g/m2 IV; thiotepa [Thioplex], 480 mg/m2 IV; and
carboplatin [Paraplatin], 1.6 g/m2 IV; with autologous stem-cell support.
Following completion of chemotherapy, both groups underwent locoregional
radiation therapy followed by adjuvant tamoxifen, 40 mg/d orally for 2
years. The two chemohormonally treated high-risk groups were compared to a
control group that consisted of 50 age-matched patients with stage I breast
cancer who had been treated with surgery and radiation therapy, but who had not
received any systemic chemotherapy. About 25% of the control group had been
treated with adjuvant tamoxifen.
Several patients declined participation in the
neuropsychological study due to the inconvenience of an additional clinic visit
with its lengthy cognitive testing session. Of the original 83 randomized
patients with high-risk breast cancer, 36 patients treated with standard-dose
chemotherapy and 34 patients treated with high-dose chemotherapy underwent
neuropsychological testing. Of the original 50 patients in the control group, 34
participated in cognitive testing. In regard to menopausal status at the time of
study entry, virtually all of the high-risk, chemohormonally treated patients
were postmenopausal. In contrast, the control group comprised 21 premenopausal
and 13 postmenopausal patients.
Neuropsychological testing included a battery of 13 standardized
tests of multiple cognitive domains, a checklist of cognitive problems in daily
life, a standardized health-related quality-of-life questionnaire, and the
Hopkins Symptom Checklist-25 to assess anxiety and depression. This extensive
cognitive function testing was administered at a single point in time at a mean
of 2 years following chemotherapy in the high-risk groups. However, at the
time of cognitive testing, patients in the control group had been off therapy
for an average of 5 months longer than the patients treated with chemotherapy.
Results: Results from the study by van Dam et al suggest
substantial cognitive deficits in the high-risk breast cancer patients treated
with adjuvant chemohormonal therapy. Cognitive impairment was found in 32% of
the patients treated with high-dose chemohormonal therapy, in 17% of the
patients treated with standard-dose chemohormonal therapy, and in 9% of
controls. Patients treated with high-dose chemohormonal therapy had an 8.2-times
higher risk of cognitive impairment than the control patients who were not
treated systemically, as well as a 3.5-times elevated risk in comparison with
the patients who received standard-dose therapy. High-risk patients who received
chemohormonal therapy expressed substantially higher self-reported cognitive
dysfunction, compared with the control group, via higher scores on the checklist
of cognitive problems in daily life.
Quality-of-life testing showed a similar decrease in patients
treated with high-dose therapy vs both standard-dose-treated and control
groups. No significant differences were found between patients treated with
standard-dose chemotherapy and the control patients in any portion of the
quality-of-life testing. High-dose chemotherapy patients had significantly
elevated scores on the depression subscale in comparison with the control group
patients, whereas the patients in all three groups had comparable anxiety
Interestingly, no relationship was found between the overall
score of cognitive impairment and the various self-reported measures. Thus, the
patients who complained of experiencing cognitive difficulty were not
necessarily the same as those who were identified as being cognitively impaired.
A strong relationship between self-reported cognitive problems and psychological
distress was found in the study by van Dam et al. This correlates with the
previous work by Cull et al, who noted no relationship between self-reported
memory difficulties in several patients with lymphoma and their performance on
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