Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.
Neurocognitive impairment is prevalent among cancer survivors, including those treated with hematopoietic stem cell transplantation (HCT) for hematological malignancies. Impairments in neurocognitive domains such as learning, mental processing, attention and executive functioning are measurable by neuropsychological testing in 41–51% of HCT recipients in the months and years after transplant.1, 2, 3, 4 Although the underlying mechanisms remain unclear5, 6 and neurocognitive deficits often pre-exist HCT,7, 8, 9 the pervasiveness of impairment following the completion of treatment is concerning. Routine monitoring of neurocognitive functioning among cancer survivors is now recommended.10, 11
Still, the everyday functional impact of neurocognitive impairment among cancer patients remains relatively vague. Although patient interviews suggest broad negative impacts on personal relationships, emotional well-being and fulfillment of professional responsibilities,12, 13, 14, 15 the specific everyday activities that may be compromised by neurocognitive deficits after cancer treatment have yet to be examined. Such an understanding may guide the development of compensatory strategies that may help patients cope with specific task-related deficits, and thus mitigate negative outcomes. This is particularly relevant given that established pharmacological or behavioral interventions to treat neurocognitive impairment after cancer treatment are currently limited.16
Medication management ability is an essential component of self-care after allogeneic HCT, whereby patient adherence to complex, and often fluctuating, medication regimens is critical for preventing post-transplant morbidity. Studies in non-cancer settings suggest that neurocognitive deficits may compromise medication management ability. Neurocognitive deficits, in patterns similar to those observed in cancer patients, have been associated with poorer medication management and adherence among persons with heart failure,17, 18 HIV/AIDS,19, 20, 21 Parkinson’s disease,22 schizophrenia23 and also community-dwelling older adults.24 Thus, the purpose of this study was to examine the consequences of neurocognitive functioning on medication management ability among patients treated with HCT.
Patients and methods
Participants were recruited between May 2012 and November 2013 as part of a prospective study of cognitive functioning after allogeneic HCT. Eligible individuals were: (1) aged 18 years or older; (2) scheduled for their first allogeneic HCT; and (3) fluent in English. After providing informed consent, participants were followed for 6 months post transplantation, except in the following circumstances under which participation was terminated: (1) withdrawal of consent; (2) participants did not receive the scheduled transplant; (3) disease relapse; or (4) death. The study was approved by the Research Ethics Board at the study site.
Study visits were conducted at three time points; within 14 days before the start of transplant conditioning (T0), 100 days after transplant (+/− 14 days) (T1) and 6 months after transplant (+/− 14 days) (T2). Participants who completed study visits at T0 and at least one other follow-up (T1 and/or T2) were included in the present analysis.
Medication management task—revised
The medication management task—revised (MMT-R) is a functional assessment of medication management ability, in which participants are presented with five different mock medications and scored on their ability to dispense the medications and answer questions based on a fictitious prescription regimen.20 Total scores on the MMT-R range from 0 to 10, with impairment on the task defined as a score of <8.20 The MMT-R was developed for use in the Central nervous system HIV Anti-Retroviral Therapy Effects Research (CHARTER) study to evaluate functional consequences of HIV-associated neurocognitive disorders.20 Construct validity of the MMT-R has been shown in HIV populations, where worse performance on the MMT-R has been associated with greater dependence on instrumental activities of daily living20 and self-reported adherence to antiretroviral medications among patients with more advanced immunosuppression.25 In the current study, Cronbach’s alpha for the MMT-R was 0.56, 0.64 and 0.63 at T0, T1 and T2, respectively. Detailed information regarding the MMT-R is available through contacting the CHARTER Group (www.charternntc.org).
Participants completed a neuropsychological battery of nine tests across three neurocognitive domains commonly affected in cancer populations:26, 27, 28 (1) learning/memory, (2) psychomotor efficiency/processing speed and (3) executive functioning/working memory (Table 1). To mitigate practice effects, alternate versions of the instrument used to measure learning/memory (that is, HVLT-R (Hopkins Verbal Learning Test—Revised)) were used at each time point. Alternate versions of the remaining measures were unavailable. For each of the tests administered, raw scores were converted to demographically standardized T-scores (M=50, s.d.=10) based on published normative data.29, 30, 31, 32, 33, 34, 35, 36, 37 Neurocognitive impairment was defined as a T-score of <35 on two tests, or <30 on one test, consistent with internationally recognized standards.28 Composite T-scores for each of the three neurocognitive domains were computed by taking the average score on two constituent tests (Table 1).
Self-reported cognitive problems
The Cognitive Failures Questionnaire38 is a 25-item questionnaire that assesses self-reported frequency of cognitive lapses. The EORTC QLQ-C30 Cognitive Subscale39 is a two-item questionnaire that assesses perceived cognitive difficulties.
Demographic and clinical characteristics
Self-administered questionnaires and clinical chart extraction were used to collect both baseline and time-varying characteristics. Baseline characteristics included age, sex, years of education, diagnosis, transplant conditioning intensity and pre-transplant comorbidities using the hematopoietic cell transplantation—comorbidity index (HCT-CI).40 Intelligence quotient (IQ) was also assessed at baseline using the American National Adult Reading Test.41 At each time point, the following were also collected: current number of medications; fatigue severity via Fatigue Subscale of the Functional Assessment of Cancer Therapy (FACT-F);42 physical symptom burden via Memorial Symptom Assessment Scale—Short Form (MSAS-SF) Physical subscale;43, 44 and depressive symptoms via Center for Epidemiological Studies—Depression (CES-D) scale.45 As a measure of functional status, Karnofsky Performance Scale (KPS)46 was also assessed at each time point using the interview method outlined by Schag et al.47 At T1 and T2, peak severity of acute and chronic GvHD as transplant was ascertained from participant medical records. Acute GvHD severity was graded in increasing severity from I to IV, using the revised Glucksberg grading system.48 Chronic GvHD was graded as mild, moderate or severe as per National Institutes of Health consensus criteria.49
Descriptive statistics were used to explore associations between neurocognitive functioning and medication management ability. Pearson’s correlations were computed between MMT-R scores and domain-specific neurocognitive performance as well as self-reported cognitive problems. t-Tests and Fisher’s exact tests were used to compare participants who met the criteria for neurocognitive impairment, to those who did not, on MMT-R raw scores and whether they met the criteria for MMT-R impairment. To identify predictors of MMT-R impairment, non-linear multi-level multivariate modeling was used including the variables that demonstrated an association with MMT-R impairment on univariate analysis at a significance level of P<0.25. Candidate variables included each domain of neurocognitive functioning, and all demographic and clinical characteristics described above. For this analysis, clinically significant cut-scores were used to dichotomize variables related to HCT-CI score (<3 vs 3),40 functional status (KPS<80 vs KPS80),47 acute GvHD (none/I vs II/III/IV)50 and chronic GvHD (none/mild vs moderate/severe).49 Multicolinearity of potential predictors was checked before inclusion into the final model; variables with a variance inflation factor of >5.0 were considered for omission.51 Statistical significance was considered at P<0.05 with no adjustment made for multiple comparisons. All statistical analyses were conducted via SAS 9.2 (SAS Institute, Cary, NC, USA).
Of the 108 patients who met the eligibility criteria and were approached for the study, 97 (90%) consented to participate. Of all 20 patients were subsequently excluded due to delay in transplant (n=15) or inability to be contacted (n=5). Of the remaining 77 participants who completed the baseline assessment at T0, 58 participants completed at least one other follow-up assessment (T1 and/or T2) and were included in the current analysis, 41 (71%) of whom provided data at all three time points. This achieved the desired sample size of 50 evaluable patients for the larger prospective study. There were no statistically significant differences between the 58 participants included in this analysis and the 19 participants lost to follow-up with respect to baseline neurocognitive functioning, self-reported cognitive problems, or demographic and clinical characteristics, or MMT-R score. Feeling too ill to participate in study measures was the main reason for non-participation at either follow-up.
Of the 58 study participants, the MMT-R was completed by 55 participants at T0, 48 participants at T1 and 42 participants at T2. Three participants did not complete the MMT-R at T0, but later completed the task at follow-up. In general, missing data for individual measures occurred for reasons unrelated to the outcome of neurocognitive functioning (for example, time limitations due to scheduling, transportation arrangements), and so were considered ‘missing completely at random’.52 Thus, for the purposes of the multi-level modeling, any available data from the 58 participants was included, without imputation of missing values.
Characteristics for the sample are shown in Tables 2 and 3. The mean age was 47.9 years (range18–70). Eighty-one percent of the participants were Caucasian. Average years of education was 13.81 (range 10–18) and average IQ was 114.18 (range 95–127). The median number of current medications at T0 was 1.0 (range 0–12), 5.0 (range 0–20) at T1 and 5.0 (range 0–12) at T2.
The criteria for neurocognitive impairment were met by 46% (26/56), 38% (19/50) and 29% (12/42) of participants at T0, T1 and T2, respectively. The criteria for MMT-R impairment was met by 42% (23/55), 40% (19/48) and 36% (15/42) of participants at T0, T1, and T2, respectively.
Correlates of MMT-R scores
Domain-specific neurocognitive performance across all domains showed modest correlations (r=0.36–0.71) with MMT-R score at each time point, with the exception of one weak correlation between MMT-R score and psychomotor efficiency/processing speed at baseline (r=0.29) (Table 4). The domain of executive functioning/working memory was most strongly correlated with MMT-R score, particularly at T2 where performance accounted for 50% (r=0.71, r2=0.50) of the variation in MMT-R score. MMT-R score was not significantly associated with self-reported cognitive problems at any time point (Table 4). In post hoc analyses, baseline MMT-R score for the 19 participants lost-to-follow-up was also significantly correlated with executive functioning/working memory (r=0.63, P=0.021), but not to any other neurocognitive domain or measure of self-reported cognitive problems.
Differences in MMT-R scores based on neurocognitive impairment
At each time point, participants who met the criteria for neurocognitive impairment had significantly lower scores on the MMT-R as compared with neurocognitively normal participants (all P<0.05; Figure 1a). Neurocognitively impaired participants were also more likely to meet the criteria for MMT-R impairment at T1 (72% vs 20%, χ2 (1)=12.83, P=0.0003) and T2 (67% vs 23%, Fisher’s Exact Test P=0.0132), but not at T0 (52% vs 33%, χ2 (1)=1.95, P=0.1623; Figure 1b). The current number of medications did not differ between those who were met the criteria for MMT-R impairment and those who did not, at any time point.
Multi-level models predicting MMT-R impairment
The multi-level model predicting MMT-R impairment is summarized in Table 5. Each of the neurocognitive domains tested was a significant predictor of MMT-R impairment on univariate analysis and entered into the final multivariate model with various confounders (Supplementary Material provides details of the univariate analysis). Multicolinearity across variables was not detected. In the final model, Executive Functioning/Working Memory was the only domain that remained a significant predictor of MMT-R impairment (odds ratio=0.89, 95% confidence interval 0.80–0.98, P=0.023), and this effect was consistent over time.
Additionally, MSAS-SF-Physical scores predicted better performance on the MMT-R, though this effect was reduced over time. At T0, the odds of MMT-R impairment was 80% lower for each unit increase in MSAS-SF Physical scores, whereas this was reduced to 39% and 46% at T1 and T2, respectively (Table 5). Myeloblative conditioning and depressive symptoms also showed non-significant trends for predicting better MMT-R performance in the final model.
In a subgroup analysis, the final multi-level model was replicated using only participants who completed the MMT-R at all three time points. In this model, the main effect of executive functioning/working memory was supported but the predictive effect of physical symptom distress was not detected. No additional variables emerged as predictors in this model.
To our knowledge, this is the first study to use a standardized, performance-based functional assessment to examine the everyday consequences of neurocognitive deficits among patients treated for cancer. Using internationally recognized criteria for defining neurocognitive impairment, we showed that patients who meet these criteria were also more likely to have impaired medication management ability on a simulated task. We also showed that of the neurocognitive domains we tested, poorer performance in executive functioning/working memory was the most strongly associated with impaired medication management ability.
Our findings provide support for the functional significance of the neurocognitive deficits demonstrated after allogeneic HCT on an instrumental activity of daily living; one’s ability to manage medications. This is consistent with existing evidence in other non-cancer clinical and community populations17, 18, 19, 20, 21, 22, 23, 24 that have shown similar associations between neuropsychological performance and medication management. In non-cancer studies, tests of executive functioning and working memory have consistently been implicated in this relationship,18, 19, 20, 21 a finding that is supported by our work. Although often considered as separate domains, executive functioning and working memory are very closely linked. Executive functioning provides the ability to engage in purposeful and goal-oriented behavior (for example, initiation, planning and decision-making), while working memory, which is closely linked to attention, provides the ability to maintain and manipulate information over a brief period of time. Both of these cognitive abilities may be essential when one has to, for example, plan, manage and make decisions surrounding complex medication regimens on a daily basis.
In this study, neither learning/memory or psychomotor efficiency/processing speed predicted medication management ability over and above executive functioning/working memory in the multivariate model, despite being shown, though inconsistently, to be independently associated with medication management in other populations.19, 20, 21, 22, 23 Varying findings regarding the effect of both learning/memory and psychomotor efficiency/processing speed in the literature may be an artifact of a number of factors, including but not limited to, small sample sizes, differences in measures used to test neurocognitive functioning and medication management ability, and unique population characteristics that might affect cognitive functioning, medication management ability and necessary confounders. Our prospective study applied an approach to neuropsychological testing recommended for a cancer population, a medication management task validated for use in a comparable clinical setting, and controlled for confounders specific to transplant recipients. As this study was the first to examine this relationship in a cancer setting, replication of this approach in a larger sample may help to clarify the nature of these particular relationships specific to this group of patients.
In our study, participants’ self-reports of their own neurocognitive functioning, were not an adequate indicator of medication management ability. These findings suggest that to identify patients having the most difficulty with managing their medication regimen, reliance on patient self-report of cognitive problems is likely ineffective and more objective assessments of neurocognitive functioning is warranted. Indeed, it has been suggested that self-reported cognitive problems are more likely a reflection of psychological distress rather than the neuropsychological performance.53
Interestingly, we found that greater physical symptom distress predicted better medication management ability, though this advantage decreased after transplant. It is possible that these participants may have been more attuned to the task of managing medications based on their experience with self-management of symptoms, particularly before transplant. Conversely, in the post-transplant period when most participants were self-administering a similar post-transplant medication regimen, the benefit of this early training could have been reduced.
The prevalence of neuropsychological impairment in this sample was 46% before transplant, three times that which would be expected in the general population.36, 54, 55 Almost a third of patients were impaired at 6 months post transplant, suggesting that cognitive functioning remains a prevalent and important issue during recovery after allogeneic HCT. The trajectory and predictors of neurocognitive functioning over this time course is an important issue that will be explored (manuscript in preparation). To explore whether predictors of medication management were related to their effect on neurocognitive functioning, multicolinearity was assessed but not detected in the final model.
The findings of our study should be interpreted in light of its limitations. First, our small sample size and missing follow-up data from ~30% of our participants may have limited our statistical power to detect a true effect. Although we did detect a significant relationship between neurocognitive functioning and medication management ability that was both consistent with findings in a non-cancer population and insensitive to missing data, further investigation in a larger sample would allow for the robust testing of potential predictors, including those that showed a non-significant trend in our limited sample. Second, the role that practice effects may have had in our results cannot be ruled out, as alternate forms of only one of our instruments was available. Increasing familiarity with the standardized tests in this study could have improved participants’ scores over time on individual tasks, including the MMT-R. However, we detected a stable relationship between executive functioning/working memory and impaired medication management ability that was independent of time of data collection. Third, our use of a simulated task in a controlled testing environment may not have fully captured participants’ ability to manage their individually-prescribed medication regimen. Research approaches incorporating indirect (for example, electronic monitoring devices) and direct (for example, plasma drug concentrations) measurements of the participants’ own medication adherence,56 can facilitate this interpretation. Finally, as we focused on the first six months after allogeneic HCT, future studies are warranted that investigate the effect of neurocognitive functioning on medication management ability among longer term survivors.
Adherence to complex medication regimens after allogeneic HCT is paramount to optimizing transplant success and minimizing transplant-related complications. Medications must be taken in the right doses, at the right time, in addition to any additional special instructions. Given the central role of medications in the medical management of post-transplant recovery, patients may benefit from routine screening of neurocognitive functioning, or at the very least, an assessment of their understanding of and adherence to medication regimens. The provision of supportive interventions to assist in medication management, such as reviewing medication lists and tracking medications taken, may mitigate negative outcomes and enhance patient safety in this respect.57
More broadly, our findings provide further evidence of the clinical significance of cancer and treatment-related neurocognitive impairment, thus highlighting the importance of developing supportive care or rehabilitative services for patients experiencing persistent deficits. Given the growing population of cancer survivors, understanding the impact of late and long-term effects, such as neurocognitive deficits, will guide the provision of patient-focused care to optimize quality of life.
Fred Banting and Charles Best Canada Graduate Scholarship – Doctoral Award, Canadian Institutes of Health Research; Rosenstadt Dissertation Award and Lawrence S. Bloomberg Faculty of Nursing were the research support. This manuscript contains original material previously presented at the annual scientific meeting of the Canadian Bone and Marrow Transplant Group in June 2014. The views expressed in this article are those of the authors and not an official position of the institution or the funders.
About this article
Supplementary Information accompanies this paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)
Neurocognitive Dysfunction in Hematopoietic Cell Transplant Recipients: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Complications and Quality of Life Working Party of the European Society for Blood and Marrow Transplantation
Biology of Blood and Marrow Transplantation (2018)