In this cross-sectional study, PCNSL patients treated with HD-MTX alone had higher scores than patients who received WBRT + HD-MTX across all neuropsychological tests, including attention, executive function, motor speed, and memory. After controlling for the effects of age and time since treatment completion, significant group differences were seen in selective attention and memory functions. These results support studies reporting that treatment with HD-MTX alone9
is not associated with severe cognitive deficits in PCNSL patients, even among the elderly. Although patients treated with chemotherapy alone did not meet criteria for cognitive impairment, mean test scores were within 1 SD
below the normative sample on most measures, including selective attention, motor speed, executive function, and verbal learning and delayed recall. These mild cognitive decrements are consistent with the described neurotoxicity associated with chemotherapy, particularly methotrexate and cytarabine22
; however, we cannot determine to what extent some of these difficulties could be disease related given the cross-sectional design. Patients treated with WBRT + HD-MTX had impairment across most cognitive tests, including selective attention, motor speed, set-shifting, verbal learning, delayed recall, and recognition memory. These findings are in agreement with studies that report a diffuse pattern of moderate to severe neuropsychological deficits in brain tumor patients treated with WBRT alone or in combination with chemotherapy,15,23
and with the delayed neurotoxicity associated with combined modality regimens.4,11,12
There were no significant changes between the initial and follow-up evaluations on any of the cognitive tests, except for an improvement in attention among patients treated with HD-MTX alone, suggesting no evidence of further cognitive decline within the relatively short follow-up period.
Consistent with the cognitive findings, patients treated with HD-MTX alone had significantly lower scores than patients treated with WBRT + HD-MTX on the FACT-BR after controlling for the effects of age and time since treatment completion, indicating more intact QoL. There was no evidence of depression in either treatment group, suggesting that mood disturbance was not a contributing factor to the cognitive test performance. Additional evaluation of QoL revealed that more than 50% of patients treated with WBRT + HD-MTX were not employed due to their disease and treatment. This finding supports observations that treatment-related cognitive deficits can be of sufficient severity to interfere with QoL in brain tumor patients who are in remission from their disease.24
The majority of patients treated with HD-MTX alone had retired prior to diagnosis; therefore, an assessment of work status was not applicable.
Extensive WM abnormalities were documented in more than 60% of patients treated with WBRT + HD-MTX and in more than 50% of patients treated with HD-MTX alone, and there were no significant differences between the groups. Patients with more extensive WM disease had greater impairments in set-shifting, learning, and delayed recall of information than patients with either no or minimal WM disease. In addition, there was an increase in WM disease between the initial and the follow-up evaluation among patients who received WBRT + HD-MTX, consistent with the reported progressive delayed neurotoxicity associated with WBRT alone or in combination with MTX.4
These findings support studies documenting WM disease in brain tumor patients who received radiotherapy and chemotherapy11
and the moderate association between WM changes and cognitive impairment found in some but not all studies.25,26
Atrophy was evident in approximately 40% of patients who received WBRT + HD-MTX and in 50% of patients treated with chemotherapy alone. There were no significant differences between the 2 groups in atrophy ratings or in cognitive test performance between patients with either minimal or no atrophy and patients with moderate to severe atrophy. The higher number of patients with atrophy in the HD-MTX alone group may be in part related to their older age.
Limitations of this study include the cross-sectional design and absence of a pretreatment baseline to evaluate the specific contribution of disease and treatment adverse effects to cognitive outcome. Possible selection bias needs to be considered, as patients were not randomly assigned to treatment type. Group differences in age and time since treatment completion are also confounders, although there were significant group differences in cognitive performance after controlling for these variables. Attrition bias may have reduced the power to detect changes at follow-up and is a significant limitation in longitudinal studies of brain tumor patients. The significantly longer time since treatment completion in patients who received WBRT + HD-MTX makes it difficult to determine whether the combined regimen, as well as its more delayed effects, may have contributed to the impaired performance in these patients. Preliminary findings from a prospective study of PCNSL patients treated with an HD-MTX–based regimen followed by dose-reduced WBRT and cytarabine27
showed pretreatment impairments in motor speed, executive function, and memory, with patients improving after induction chemotherapy and remaining relatively stable for up to 2 years posttreatment.28
These data suggest that WBRT dose may play an important role in contributing to the cognitive impairment associated with the combined regimen.
The results of this study confirmed our previous findings16
and provided further evidence that PCNSL patients treated with WBRT + HD-MTX develop diffuse cognitive impairments of sufficient severity to interfere with QoL, while patients treated with HD-MTX alone had relatively more intact cognitive functions, at least at short posttherapy intervals. The importance of including standardized and sensitive cognitive tests in prospective clinical trials of PCNSL patients has been recognized.15,29
Randomized collaborative studies including neuropsychological assessment are needed to evaluate the relationship between disease control, treatment modality, survival, cognitive functions, and QoL in order to guide treatment choices. Moreover, as cognitive dysfunction often interferes with QoL, including the ability to return to work, the development and early implementation of appropriate intervention strategies to minimize or prevent these adverse effects are needed. Recent studies have begun to explore potential pharmacological and rehabilitation strategies for treatment-related neurotoxicity in brain tumor patients.30
Conflict of interest statement. Genentech Scientific Advisory Board (Drs. Correa, DeAngelis, Omuro). Hoffmann-La Roche Inc, Merck, Curatio CME, Educational Concepts, Inc (Dr. Abrey).