An extreme form of focal radiotherapy used to treat many benign and neoplastic cranial conditions is stereotactic radiosurgery (SRS). SRS uses multiple radiation beams and is able to encompass treatment volumes in the high-dose region with small margins because of the stereotactic imaging and immobilization. This results in rapid dose falloff, allowing greater sparing of normal brain tissues, and therefore minimizes risk to the surrounding structures. The cognitive impact of SRS was evaluated in a prospective trial assessing 95 patients with cerebral arteriovenous malformations with extensive neuropsychometric testing before and after SRS (median dose: 20 Gy in one fraction) and found all measures of cognitive function were stable or improved 3 years after SRS.36
The impact of WBRT on cognitive function is best addressed by prophylactic cranial irradiation (PCI) trials because, by definition, these patients should not have brain metastases (and, therefore, tumor progression is less of a confounding variable). PCI has been shown to decrease the development of brain metastases and improve cure rates and survival for small-cell lung cancer patients because of the propensity of these patients to develop brain metastases. Similar to low-grade brain tumors, a number of retrospective studies have raised concerns of neurotoxicity after PCI, but these studies have been compromised by the use of large, unconventional fraction sizes, comorbid conditions (known brain metastasis), high total doses (up to 50 Gy), concomitant use of chemotherapy, and, most importantly, lack of baseline neuropsychological testing (prospective cognitive studies have shown up to 97% of limited stage small-cell lung cancer patients have evidence of cognitive dysfunction prior to PCI).37,38 Two of the largest randomized trials of PCI did incorporate prospective neuropsychometric testing and both found a significant proportion of patients had cognitive dysfunction at baseline, but found no differences in cognitive performance between the randomization arms of PCI or no PCI.39,40 However, higher doses of PCI are associated with worse cognitive outcomes; a randomized trial of different radiation schedules found greater rates of cognitive decline in patients treated with 36 Gy compared to patients treated with 25 Gy.41 Finally, in patient populations with a low incidence of brain metastases, the risk–benefit ratio of PCI shifts and is less favorable. A phase 3 trial of PCI for patients with non–small-cell lung cancer found worse function on some measures of cognitive function in those patients treated with PCI compared to the observation arm. However, the 1-year rate of brain metastases was only 18% in the observation arm—much lower than would be expected with small-cell lung cancer, where 50 to 60% of patients develop brain metastases if they do not receive PCI.42,43 Therefore, it should be recognized that PCI does have a risk, but in high-risk populations such as those with small-cell lung cancer, the risk of brain metastases and associated decline with growing intracranial lesions outweighs the cognitive risk of PCI.
More recently, there have also been prospective trials with extensive cognitive testing for patients with brain metastases treated with WBRT. One of these studies, an international phase 3 trial, prospectively evaluated cognitive function in 135 patients with brain metastases before and after WBRT and found tumor progression was the predominant cause of cognitive decline, with stable or improving cognitive function in long-term (i.e., 15-month) survivors.14 A smaller German trial assessed 15 patients with brain metastases with a 90-minute battery of cognitive tests before and after WBRT (40 Gy in 2-Gy daily fractions) and found stable cognitive function in long-term survivors.44 On the other hand, in a recent study comparing SRS alone to SRS and WBRT for 58 patients with up to three brain metastasis, 49% of patients in the WBRT group experienced declines in learning and memory at 4 months compared to only 23% in the SRS group.45 Critics note the small size of the single-institutional study and a substantial difference in survival in the two groups, suggesting that the patients may not have been well-matched for prognostic factors.46 Additionally, at 4 months, cognitive function after radiotherapy is at a nadir due to subacute or early-delayed effects of radiotherapy that gradually resolve over time.47 Recognizing the limitations of this trial, it does suggest that for patients undergoing radiosurgery for a relatively small burden of intracranial disease followed closely with MRI, delay or avoidance of WBRT may be reasonable and may result in better cognitive function over time.
Radiotherapy techniques may impact the cognitive risk of WBRT. For example, large fraction sizes, as delivered in many historical studies, have been associated with dementia and cognitive decline in long-term survivors after WBRT; therefore, dose-fractionation schedules should be determined by the patient’s estimated prognosis, with more protracted schedules used for patients with the possibility of long-term survival.38 Another approach is to modify the WBRT to avoid sensitive regions of the brain. It has been suggested that hippocampal neural stem cell injury from WBRT may play a role in memory decline.48 Intensity-modulated radiotherapy can be used to conformally avoid the hippocampal neural stem cell compartment during WBRT (HA-WBRT). The Radiation Therapy Oncology Group (RTOG) conducted a single-arm phase 2 study of HA-WBRT for 113 patients with brain metastases.49 Only 4.5% of patients experienced progression within the hippocampal avoidance region consistent with prior retrospective studies.50 The mean relative decline in verbal memory at 4 months was 7%, which was significantly lower in comparison to the historical control of 30% at 4 months (p = 0.0003).
In summary, although WBRT and PCI prospective trials suggest that, on the whole, any detrimental effects on cognitive function from radiotherapy seem to be balanced by the beneficial cognitive effects of improved tumor control in the brain, this must be balanced with selecting the proper patient population and weighing out the risk–benefit ratio. Modification of WBRT techniques such as hippocampal avoidance presents an intriguing treatment approach, although further study is needed.
Chemotherapy
The last decade has seen a surge in research on cognitive functioning following diagnosis and treatment of non-CNS cancer. An emerging body of data show that a subgroup of cancer patients is vulnerable to posttreatment (mostly but not exclusively chemotherapy related) cognitive decline, which has a significant impact on quality of life and daily function.51–55 Chemotherapy is widely used in patients with non-CNS cancer and is known to be harmful to multiple organ systems. Traditionally, the CNS has been considered to be less vulnerable to the toxic effects of chemotherapy; however, acute and delayed neurologic complications are being identified with increasing frequency. Human and preclinical studies into the occurrence and determinants of cognitive decline in non-CNS cancer patients have led to a growing consensus that many chemotherapeutic agents for non-CNS cancer can interfere with various neurobiologic processes and can induce cognitive impairment.56,57
Incidence and Pattern of Cognitive Decline
Cognitive dysfunction has been particularly well studied in breast cancer patients undergoing adjuvant systemic therapy. The majority of the prospective studies in this patient population have indicated that 20% to 60% of patients have cognitive decline after chemotherapy compared to pretreatment cognitive performance.54,55 In addition, several neuropsychological studies have demonstrated that cognitive impairment may already be present in cancer patients before the start of treatment.58–61 Psychological distress, fatigue, or surgical factors (in case the assessment took place postsurgery) do not completely explain the possible link between cancer and cognitive dysfunction. Proposed causes for pretreatment cognitive dysfunction include not only the biology of cancer (inflammatory responses triggering neurotoxic cytokines) and common risk factors for the development of cancer and cognitive decline (e.g., poor DNA repair mechanisms linked to cancer and neurodegenerative disorders), but also methodologic considerations (patients participating in cognitive studies may not represent a random sample of individuals confronted with cancer).62,63
Patients show changes from pre- to posttreatment on a wide range of standardized neuropsychological tests. On the basis of studies with comprehensive neuropsychological examinations, a pattern of cognitive impairment can be described. Patients frequently demonstrate learning and memory deficits possibly secondary to impairment of encoding or initial processing of information and the retrieval of stored information, and diminished speed of information processing and reduced executive functioning. These changes in cognitive function have been associated with adverse impacts in cancer survivors’ daily life (e.g., work-related disabilities).64
Trajectory of Cognitive Decline
The majority of prospective studies have demonstrated cognitive dysfunction up to 1 to 2 years postchemotherapy.65 Cross-sectional studies with long-term cancer survivors show the presence of cognitive differences between chemotherapy-treated patients and noncancer controls up to 20 years posttherapy, suggesting the persistence of cognitive impairment over the years.66,67 But, mature follow-up data from prospective studies are lacking to ascertain these changes from the baseline state and to determine the slope of cognitive changes over the course of years. This is relevant, because current insights into the mechanisms of chemotherapy-induced neurologic complications raise the possibility of chemotherapy-associated premature and accelerated cognitive aging.68 Whether patients treated with chemotherapy are at risk for developing new late-onset cognitive dysfunction or dementia is not known. Several retrospective studies have been published examining the risk of dementia in breast cancer survivors who completed cytotoxic treatment up to 15 years previously using data from the linked Surveillance, Epidemiology and End Results (SEER)–Medicare database. None of these studies showed clear evidence for the existence of such a relationship, but several important methodologic issues limit the validity and interpretation of the studies.66
Risk Factors
The finding that subgroups of patients experience posttreatment cognitive decline has led to the examination of patient- and disease/treatment-related risk factors for cognitive change.69 There are some indications for a dose-response relationship based on a study that observed more patients with cognitive decline following high-dose chemotherapy compared to conventional dose chemotherapy and on a study showing a linear decline in cognitive performance after each cycle of chemotherapy.70,71 Also, several studies have pointed to a higher frequency of cognitive dysfunction in breast cancer patients receiving both chemotherapy and endocrine therapy compared to breast cancer patients treated solely with chemotherapy or endocrine treatment.55 Plausible patient-related risk factors such as age, intelligence quotient (IQ), baseline cognitive function, presence of comorbid conditions, and a host of other factors such as depression, anxiety, stress, fatigue, and treatment-induced menopause have not been identified as strong contributors to the impact of chemotherapy on cognitive function. A limited number of studies also looked at genetic factors (e.g., vulnerable alleles of genes such as APOE and COMT allele) as an explanation for why only a subgroup of patients seem to be more vulnerable for treatment-associated cognitive decline. In a study among lymphoma and breast cancer survivors, it was shown that survivors with at least one E4 allele scored lower on several cognitive tasks as compared to survivors who did not carry an E4 allele.72 Another study found that breast cancer patients who had the COMT-Val allele and were treated with chemotherapy performed more poorly on several neuropsychological tests as compared to those with the COMT-Met allele.73
Based on experimental animal studies, other blood-based biomarkers that may mediate chemotherapy-associated cognitive decline are circulating proinflammatory cytokines. Up to now, studies in cancer patients show only weak correlations between interleukin 1B (IL-1B), IL-6, and tumor necrosis factor alpha (TNF-α) levels and cognitive impairment and suggests that the role of cytokines in postchemotherapy cognitive decline is not well understood and requires further evaluation.63
Neural Substrate
Structural, functional, and molecular imaging studies in non-CNS cancer patients are helping to clarify the neural basis and have started to shed light on the brain alterations that may be part of the mechanisms underlying the observed cognitive dysfunction.74–77 White matter pathology has been observed within months and after 10 years posttreatment, both following high-dose and standard-dose regimens. Studies using voxel-based morphometry have reported volume reductions of white and grey matter 1 year and also at 20 years after the completion of chemotherapy.78,79 A prospective study observed a decrease in focal gray matter volume 1 month after cessation of chemotherapy, which recovered in some but not in all regions at 1 year posttreatment.80 The cerebral white matter seems particularly vulnerable to the effects of chemotherapy. Prospective studies investigating cerebral white matter integrity using diffusion tensor imaging reported lower fractional anisotropy (FA) in the genu of the corpus callosum, lower FA in the frontal and temporal white matter, and higher mean diffusivity in the frontal white matter of breast cancer patients who received standard-dose anthracycline-based regimens compared to breast cancer controls and healthy controls.81 In cross-sectional studies conducted, on average, 10 and 20 years after the completion of chemotherapy, comparable indications for affected white matter tracts in breast cancer patients who received chemotherapy compared to subjects without a history of cancer or breast cancer patients who never received chemotherapy were observed.78,79 Importantly, several studies have demonstrated a link between the abnormal microstructural properties in white matter regions and the cognitive impairments seen in breast cancer patients treated with chemotherapeutic agents.81 The observed changes in diffusion tensor imaging (DTI) parameters may be related to demyelination of white matter axons or axonal injury after chemotherapy. Functional MRI (fMRI) studies have demonstrated postchemotherapy changes in brain activation and in resting brain connectivity pattern. The prospective fMRI studies show a complex picture with both hyper- and hypoactivation patterns and inconsistent findings with regard to accompanying changes in fMRI task performance.76
Underlying Mechanisms
A large number of studies in rodent models have extended our understanding of the cell biology and molecular basis underlying chemotherapy-associated CNS toxicity. Moreover, patterns of behavioral performance in animals seem to correspond to a significant extent with cognitive patterns in patients, supporting the important role for preclinical research in understanding the cognitive effects of cancer treatments in humans. Using detailed cell lineage–based approaches, it has been shown that neural progenitor cells, which are the direct ancestors of all differentiated cell types in the CNS, and mature postmitotic oligodendrocytes are the most vulnerable cell populations to the effects of multiple chemotherapeutic agents.48,56,57,82,83 It has been hypothesized that long-term cognitive decline in cancer survivors is the result of a combination of decreased proliferation of neural progenitor cells, impaired hippocampal neurogenesis, and damage to oligodendroglial cells and white matter tracts.
As many different chemotherapeutic agents seems to have similar effects on the CNS, studies are also exploring common indirect mechanisms as etiologic factors of chemotherapy-associated neurotoxicity, such as pro-oxidative effects, toxic neurotranmitters/monoamine release, disruption of blood vessel density and supply, and inflammation.57
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
