Abstract
Background: Chemotherapy has been shown to cause brain changes and to compromise cognitive function in cancer survivors. Knowledge about this matter is of vital importance for good clinical practice and insights into neurological aging. However, most studies have been conducted among breast cancer patients. Less is known about the effects of chemotherapy on the cognitive function of lymphoma patients.
Material and method: We studied patients with non-Hodgkin or Hodgkin lymphoma who had been treated with standard dose chemotherapy or with supplementary high dose chemotherapy when standard dose chemotherapy had been unsuccessful. Age- and sex-matched relatives and friends were invited to participate as control participants. All participants underwent a cognitive examination with a battery of validated neuropsychological tests.
Results: Matching of patients with control participants was found to be successful. Regression analysis did not reveal worse cognitive functioning of patients (N = 106) compared to matched controls (N = 53) on the overall group level (All Bonferroni-Holm corrected p-values >0.05). However, a subgroup of 16% of patients had deviant performance according to a chance-corrected criterion based on Ingraham and Aiken's probability curves, i.e. 1.5 standard deviations below the norm on three of 14 tests. Exploratory analyses showed that this subgroup of patients was lower educated and had lower estimated premorbid intelligence.
Conclusion: Chemotherapy may compromise the function of the brain in a subgroup of lymphoma patients. We hypothesize protection of the brain by ‘cognitive or brain reserve’ as a possible explanation.
Chemotherapy has improved the outcomes for patients with cancer markedly [Citation1]. However, besides well known immediate side effects, such as nausea, chemotherapy has also been associated with long-term negative consequences, such as cardiovascular disease [Citation2] and the potential neurotoxicity of chemotherapy [Citation3,Citation4] through possible disturbance of various mechanisms including apoptosis and suppressed neurogenesis [Citation5].
Cognitive sequelae of chemotherapy have been demonstrated by objective and validated neuropsychological tests [Citation3,Citation6] with incidences ranging from 19% to 78% across different studies [Citation3]. Cognitive domains that were most likely to be affected included learning, memory, processing speed and executive function. Importantly, these findings were corroborated by brain imaging studies which reported smaller gray matter and white matter volumes [Citation7], white matter integrity changes [Citation8], and hypo-activation in various regions of the brain [Citation9].
Insight into cognitive impairment caused by neurotoxic effects of chemotherapy is needed from the perspective of good clinical practice, e.g. the optimization of the dosing of chemotherapy regimens by minimizing their harm while maintaining treatment efficacy [Citation5], knowledge of the impact of such neurotoxic effects on patients’ functioning in everyday life including their vocational careers [Citation10,Citation11], and adoption of cognitive rehabilitation interventions in routine clinical practice [Citation12]. Furthermore, from a neuro-epidemiological perspective, it is important to examine whether treatment with chemotherapy in (late) adulthood accelerates cognitive decline and increases the risk of dementia. A previous study of breast cancer patients showed that treatment with chemotherapy was associated with reductions in overall gray matter volume about 20 years later [Citation13].
Hitherto, cognitive sequelae of chemotherapy have been studied predominantly in breast cancer survivors [Citation3] and only to a limited extent in other patient populations for whom chemotherapy is an important treatment strategy, such as adult lymphoma patients [Citation10,Citation14]. This is an important knowledge gap because the incidence of lymphoma was found to be 2.8 per 100 000 individuals per year and the treatment of lymphoma has a high success rate [Citation15].
In this study, we will therefore examine cognitive sequelae of chemotherapy in adult lymphoma patients as assessed with objective neuropsychological tests. We will compare patients with ‘age- and sex-matched’ controls on the overall group level. We will also examine a ‘dose-response relationship’ by distinguishing patients who were treated with standard dose chemotherapy from those for whom standard dose chemotherapy was unsuccessful and who were therefore treated with supplementary high dose chemotherapy. In addition, because not all patients may be equally affected [Citation4], we will also examine whether a subgroup of patients have deviant cognitive function. If so, we will explore possible neuro-epidemiological differences such as protective ‘cognitive reserve’ [Citation3,Citation4,Citation16] and younger age [Citation10] between patients with deviant cognitive function and patients with normal cognitive function.
Material and methods
Participants and eligibility criteria
Data were collected between 2000 and 2002 from patients with Hodgkin or non-Hodgkin lymphoma who had been treated with chemotherapy in hospitals in the Netherlands. If standard dose chemotherapy turned out to be insufficiently effective, patients were treated with supplementary high dose chemotherapy.
We excluded patients with the following confounding etiology: a history of central nervous system (CNS) disease, dyslexia or color blindness, traumatic brain injury or a whiplash in the past five years. Age- and sex-matched relatives and friends were invited to participate as control participants. Standard dose chemotherapy included usually 6–8 cycles of the following (or related) therapeutic schemes: CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 and vincristine 1.4 mg/m2 intravenously administered on the first day and prednisolone 50–100 mg/m2 orally on the 1st–5th day for non-Hodgkin lymphoma; MOPP-ABV (mechlorethamine 6 mg/m2 and vincristine 1.4 mg/m2 intravenously administered on the first day, procarbazine 100 mg/m2 orally taken on 1st–7th days, prednisolone 40 mg/m2 orally on 1st–14th days, adriamycin 35 mg/m2, vinblastine 6 mg/m2, and bleomycin 10 mg/m2 intravenously administered on the eighth day for Hodgkin lymphoma). High dose chemotherapy consisted of one cycle of the BEAM therapeutic treatment scheme (carmustine 300 mg/m2, etoposide 200 mg/m2, cytarabine 200 mg/m2 on 2nd–5th days, melphalan 140 mg/m2 for non-Hodgkin lymphoma) after induction therapy.
For patients, we assessed the following clinical characteristics: cytostatic therapeutic scheme, time since completion of chemotherapy, and whether patients had been treated with radiation therapy. We also assessed participants’ sex, age, educational level (assessed on an eight-point scale: 1, lower elementary education; 8, university). Procedures were in accordance with the Helsinki Declaration of 1975, as revised in 1983. The medical ethical committee approved the study and all patients gave informed consent.
Neuropsychological outcomes
Participants’ cognitive function was examined using a standardized neuropsychological test battery consisting of nine tests (25 test indices) covering the domains of information processing/short-term memory/psychomotor speed and attention, executive function, verbal/visual memory, and language (See Appendix for a description of tests). The choice of tests was based on their sensitivity to subtle deficits to functioning in a cognitive domain, reliability and validity. The Dutch Adult Reading Test was used as a measure of premorbid intelligence as it was previously shown that word reading ability is relatively independent of brain dysfunction [Citation17]. Based on participants’ preferences, the neuropsychological examination took place in their homes or in the hospital. All tests were administered in the same order to every participant. During the examination, participants were also asked to complete questionnaires about mood and anxiety problems in everyday life (see below). The total examination took on average 2.5 hours.
Mood, anxiety and problems in daily life
An abbreviated version of the Hopkins Symptoms Checklist (HSCL) was used to assess mood (15 items) and anxiety (10 items). We assessed health-related quality of life with regard to physical, cognitive, and emotional functioning as well as fatigue using relevant items from the questionnaire of the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30).
Statistical analysis
We compared patients and control participants on the specific neuropsychological tests. Subsequently, we examined ‘dose-response relationships’ by studying whether patients who were treated with supplementary high dose chemotherapy, following treatment with standard dose chemotherapy, had more neuropsychological deficits compared to patients who had been treated with standard dose chemotherapy only and control participants. Mean differences on the specific neuropsychological tests were examined with linear regression analysis. In all relevant analyses, we adjusted for covariates on which the groups significantly differed. Owing to the large number of comparisons, standard one-sided p-values <0.05 were corrected using a flexible Bonferroni-Holm procedure.
Finally, we examined whether a subgroup of patients had deviant cognitive function below a critical threshold on the different neuropsychological tests studied. However, with an increasing number of measures, the likelihood increases that a deviant result is a mere chance finding. To control for chance capitalization, we adopted the formula and corresponding probability curves presented by Ingraham and Aiken [Citation18]. Based on their formula, we judged performance of 1.5 standard deviations below the mean on at least three of 14 test indices to not exceed 5% probability at the multivariate level. We therefore restricted this particular analysis to the following tests which we deemed most sensitive to effects of chemotherapy: Stroop Test: color-word interference and partial color-word interference conditions; the mean score of animal and profession fluency; digit symbol substitution; WMS visual delayed memory; Trail making Test: Part A and B; Verbal Learning Memory Test: long delayed recall, cued delayed recall; Finger Tapping Test: mean and standard deviation of the dominant hand; Eriksen Task: early selective attention, late selective attention, and sustained attention (See Appendix for a description of tests, available online at http://www.informahealthcare.com). Subsequently, descriptive statistics were computed to explore whether patients who had deviant cognitive performance at the multivariate level differed from the other patients with regard to demographic and clinical characteristics.
Results
Of the 200 eligible patients and control participants, a total of 171 consented to participate (response rate 86%). For the present analysis, another 12 participants were excluded for the following reasons: CNS disease (N = 2), whiplash in the past five years (N = 1), dyslexia (N = 4), and color blindness (N = 5), leaving data from a total of 159 participants available for analysis. Of these participants, 106 were patients and 53 were matched controls. shows the demographic and clinical characteristics of the participants. Lymphoma patients were well matched with control participants with regard to percentage of women, mean age, mean educational level, and mean estimated premorbid intelligence.
Table 1. Mean differences between control participants and patients on demographic characteristics, estimated premorbid intelligence, and mood and health-related quality of life.
Multiple regression analyses showed that compared to matched controls, lymphoma patients reported more anxiety, more problems with regard to physical, cognitive, and emotional function, as well as more fatigue (See ). Findings on neuropsychological tests are presented in . At the group level, only small differences were observed between matched controls and patients. None of the differences were significant as all p-values were greater than the Bonferroni-Holm adjusted alpha threshold (0.05/27 tests ∼ adjusted threshold 0.0018). When distinguishing patients who had been treated with high dose chemotherapy following standard dose chemotherapy from patients who had been treated with standard dose chemotherapy only, and comparing both patient groups with control participants, again none of the differences were significant (data and results available on request).
Table 2. Mean differences between control participants and patients on neuropsychological testsa,b.
Turning to the findings about whether a subgroup of patients performed worse than matched control participants, we found 17 patients (16%) to have a deviant performance of at least 1.5 standard deviations below the mean of control participants on at least three of 14 neuropsychological test indices. Descriptive analyses suggested that compared to the other patients, patients with deviant cognitive functioning at the multivariate level had been lower educated (M = 2.5, SD =0.9 vs. M = 4.3, SD =1.9 on an eight-point scale), had lower estimated premorbid intelligence (Mean DART scores: 87.3, SD =9.8 vs. 98.4, SD =16.8), were older (Mean age =56.6, SD =10.2 vs. Mean age =45.5, SD =12.3) and were more often male (65% vs. 52%). Patients with deviant cognitive function did not differ or differed only minor from the other patients with respect to months since completion of chemotherapy (M = 51, SD =24.8 vs. M = 55, SD =30.6), percentage of patients treated with high dose chemotherapy (24% vs. 25%), percentage of patients treated with radiation therapy (63% vs. 65%), anxiety (HSCL anxiety score: M = 14.1, SD =11.8 vs. M = 13.0, SD = 11.5), depression (HSCL depression score: M = 15.9, SD = 10.7 vs. M = 13.8, SD = 13.9), and EORTC QLQ-C30 scores of physical function (M = 83.9, SD = 14.5 vs. M = 88.2, SD = 12.9), self-reported cognitive function (M = 74.5, SD = 16.8 vs. M = 78.1, SD = 22.1), emotional functioning (M = 77.4, SD = 15.2 vs. M = 78.5, SD = 18.1) and fatigue (M = 66.0, SD = 17.3 vs. M = 69.8, SD = 21.8).
Discussion
Apart from the 16% of patients who had deviant neuropsychological performance, there were no differences between lymphoma patients exposed to chemotherapy and ‘age- and sex-matched’ controls on a wide array of objective neuropsychological tests. This observation is in line with results from previous studies that were predominantly conducted among women with breast cancer and which showed a subgroup of patients to have cognitive impairment after treatment with chemotherapy [Citation3].
At the same time, our subgroup was smaller than typically found in previous studies. Possibly, our subgroup of patients with deviant cognitive performance had been larger closely after completion of chemotherapy and perhaps several individuals had already recovered from cognitive impairment. Consistent with this explanation was that the median time since completion of chemotherapy was approximately 55 months for our participants at the time of neuropsychological testing, whereas assessments of cognitive function in other studies took place sooner after chemotherapy completion [Citation7,Citation8,Citation16]. However, such an explanation does not simply rule out future cognitive impairment as previous studies also showed chemotherapy to be associated with cognitive impairment approximately 10 years later [Citation10] and reductions in total brain volume and overall gray matter volume approximately 20 years later [Citation13]. Clearly, longitudinal studies with a baseline neuropsychological examination before initiation of chemotherapy and neuropsychological examinations on both the shorter and longer term after completion of chemotherapy are needed in order to precisely locate the time window(s) when cognitive impairment occurs.
Another important observation was that the cognitive impairment identified for a subgroup of patients did not seem to be related to self-reported cognitive complaints, because the subgroup of patients with deviant cognitive performance did not report substantially more cognitive complaints than the other patients. This analysis clearly underlines the importance of assessing cognitive functioning using validated neuropsychological tests in addition to merely relying on self-reported cognitive functioning.
We can only speculate about potential explanations for the observation that the cognitive function of only a subgroup of patients was affected. Given that patients treated with high dose chemotherapy were not overrepresented in this subgroup of patients, exposure to high dose chemotherapy is an unlikely explanation. The explanation that ‘cognitive or brain reserve’ owing to, e.g. formal education [Citation19,Citation20] offers protection to insult of the brain by neurotoxic effects of chemotherapy is more plausible because our subgroup of patients with deviant cognitive function had lower educational and premorbid intelligence levels. However, owing to the lack of a baseline neuropsychological examination before the initiation of chemotherapy, we cannot be sure whether the deviant cognitive function of the subgroup occurred after chemotherapy exposure or whether it was already there and was thus of a preexistent nature. More research is therefore needed to test the ‘cognitive reserve hypothesis’ in cancer survivors. Similarly, given that the subgroup of patients with deviant cognitive performance were older, the question whether older age makes cancer survivors more vulnerable to effects of chemotherapy deserves further consideration too [Citation21].
Particularly for the subgroup of patients with cognitive problems, knowledge about the effects of chemotherapy on cognitive function is likely to contribute to a further optimization of chemotherapy regimens by minimizing their harm while maintaining their best achievable efficacy, to better inform, educate and counsel this subgroup of patients with cognitive problems about the effects of chemotherapy on the brain and the possible consequences with regard to functioning in daily life, e.g. at work, as well as the adoption of cognitive rehabilitation interventions.
This study had several strengths. The most important strength was that patients and control participants were well matched with respect to sex, age, educational level and estimated premorbid intelligence. Furthermore, patients with confounding etiology, such as a history of CNS disease, were excluded. For these reasons, confounding bias is not very likely. Another important strength was the assessment of cognitive deficits using a comprehensive battery of validated neuropsychological tests instead of relying on mere self-reported cognitive complaints. With regard to the analysis, an important strength was the adoption of multiple methods to compare patients with controls, i.e. overall group level comparisons and identification of a subgroup of patients with possible deviant cognitive functioning and in turn a more balanced view on potential cognitive sequelae of chemotherapy. Given that we recruited participants from various sites and that we observed ample spread in demographic and clinical characteristics, selection bias seems also not very likely. Finally, our sample size was also sufficiently large and at least not smaller than those from previous studies in which associations between exposure to chemotherapy and cognitive function were documented.
Potential shortcomings of this study should of course not be omitted. The main limitations of this study were its cross-sectional nature, the absence of a baseline neuropsychological examination prior to the initiation of chemotherapy, and the absence of neuroimaging data to assess functional and structural brain alterations. Ideally, the previously recommended longitudinal research of lymphoma patients should therefore also include neuroimaging measures. The fact that the data were collected approximately 15 years ago is not so much of a limitation, because the cytostatic therapeutic schemes have not changed much over the years and many patients were treated with these cytostatic therapeutic schemes after all.
Taken together, for a subgroup of lymphoma patients, this study reports cognitive impairment which possibly occurred after chemotherapy treatment. The ‘cognitive reserve hypothesis’ as well as the window of time when cognitive deficits of chemotherapy occur, are worthwhile to test in future longitudinal research.
APPENDIX
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