Impact of Cancer Treatment on Cognitive Function: A Systematic Review of Data in Hematological Malignancies in

The association between Abstract Cognitive function refers to the activities of the brain necessary to generate complex behaviors for day to day tasks. A significant proportion of patients with cancers including hematologic malignancies might present with some degree of baseline cognitive dysfunction prior to treatment. With clinical advances and emerging treatment strategies, we are currently more able to treat older adult population. Consequently, we are encountering various side effects including long-term neurocognitive sequelae. Cognitive dysfunction may present as impaired concentration, impaired memory or difficulty in carrying out multiple tasks independent of disease status. Cognitive sequelae not only affect the quality of life but also pose an additional challenge in disease management. Studies have also demonstrated an association between chemotherapy and neurodegeneration leading to acceleration of the age-related cognitive decline. The purpose of this article is to review the impact of chemotherapy along with radiotherapy and stem cell transplant on cognitive functions. Most studies focus on effects of radiotherapy on childhood acute lymphoblastic leukemia (ALL) and Primary Central Nervous System (CNS) lymphoma. In this review, we have made an attempt to identify the risk factors, manifestations, possible hypotheses for the impaired cognition in Acute Leukemia, Myelodysplastic syndromes, Lymphomas, Multiple Myeloma and stem cell transplant recipients. Possible interventional strategies to prevent and reverse cognitive decline are also discussed. allogeneic hematological

white matter integrity causing dysregulated neurogenesis to have been described in various studies [3,4]. Chemotherapy and cranial radiotherapy are known to cause neurocognitive deficiencies leading to impaired attention, learning, memory, and speed of processing information [5]. These can last for months or years after treatment and range from mild to severe [6]. The purpose of this review is to summarise the effects of chemotherapy with or without radiotherapy and stem cell transplant on various cognitive domains in adults with various hematological malignancies.

Cognitive Domains
Neurocognitive disorder comprises a group of clinical syndromes characterized by loss of previously acquired cognitive functions which affect personal, social and occupational aspects of life [7]. Cognitive domains evaluated for neurocognitive status include attention and concentration, perceptual processing, learning and working memory, abstract thinking and executive function, language, information processing speed, motor functions and emotions [8].
Consequently, there are an increasing number of adult survivors with a history of childhood ALL with long-term side effects. There is compelling evidence to suggest an association between cranial radiation for ALL and cognitive decline in adult survivors [11].
A cross-sectional study by Armstrong, et al. [11] evaluated 265 survivors of childhood ALL by using Wechsler Memory Scale IV for four memory domains: immediate, delayed, auditory and visual.
Eighty-five of them also underwent a structural and functional assessment by magnetic resonance imaging (MRI). The mean age of subjects was 37.7 years and median time from cranial radiotherapy (CRT) was 30 years. The number of patients grouped into high dose CRT (24Gy; n-138) and low dose CRT (18Gy; n-127) was not significantly different. Ninety-five percent of them had intrathecal methotrexate (MTX) and 75% had exposure to intravenous (IV) MTX. Due to evolving treatment strategies over the years, patients who received 24Gy CRT were older than the 18Gy group. However, memory battery scores were age-adjusted for direct comparison.
Compared with age-adjusted normal controls, the 24Gy group had significantly increased impairment in immediate and delayed memory and scored very low on Brief Cognitive Status Exam (BCSE) indicating reduced cognitive status. The18Gy group did not reflect these findings suggesting a dose-response effect. Immediate memory impairment was associated with smaller bilateral temporal lobe volumes. Impaired delayed memory was associated with thinner parietal and frontal cortices.
As a result of CRT associated cognitive decline, chemotherapyonly protocols have evolved, and CRT is used for the highest risk patients. Approximately 30% of children chemotherapy only regimens experience some degree of cognitive decline when compared to healthy controls [12]. Recent studies have suggested that neurocognitive dysfunction after MTX treatment is a result of altered metabolism of chemotherapy due to genetic polymorphisms [13]. A study by Elens, et al. [14] identified cerebrospinal fluid

Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Anemia associated with fatigue and cognitive dysfunction is seen in numerous cancers. Previous studies have reported the association between low hemoglobin and its effect on fatigue and cognitive function. One study reported a smaller subset of patients experiencing poor attention and visual memory when hemoglobin levels dropped below 12g/dL [16]. Another study reported difficulty in concentrating and lower processing speed at a hemoglobin level of less than 8g/dL [17]. A cross-sectional study by Wood, et al. [18] investigated the level of hemoglobin decline causing cognitive dysfunction using cutoff values 12, 10, and 8g/ dL in 55 AML and MDS patients. This study confirmed the findings of previous research that anemia does affect functional aspects of DOI: 10.26717/BJSTR.2020. 26.004349 frontotemporal lobe by demonstrating impaired immediate and delayed word retrieval, divided attention and working memory, and fine motor dexterity. However, the effects in moderate and severe anemia groups were more pronounced as compared to the mild anemia group. This study concluded that a hemoglobin level of 10 g/dL or below is associated with changes in cognitive functioning. In    with mild symptoms of frontal and subcortical brain deficits [24].

Chronic Myeloid Leukemia (CML)
Schiebel, et al. [23] showed similar findings with IFN -α causing deficiency in information processing and frontal lobe executive functions. This study also confirmed that depression is one of the side effects of IFN-α, however, correlation between depression and cognitive measures were not significant [23]. dose of thoracic radiation. Forty-five percent of survivors were found to be impaired on tests of memory, 43% on tests of processing speed and 27% on tests of attention and 25% on executive function without any significance of radiation dose [28]. Anthracyclines have been implicated in cognitive decline when used to treat other malignancies [29]. Krull, et al. [28] hypothesized that thoracic radiation induced cardiovascular side effects leads to central nervous system morbidities leading to cognitive decline.

Hematopoietic Stem Cell Transplant (HSCT)
Autologous HSCT prolongs disease free survival and allogeneic predictors for subsequent cognitive decline [30].
The eligible age group for allogeneic HSCT is widened.
Transplant is now being offered for patients who are older than 65 years of age. A recent survey showed that gathering information about neurocognitive dysfunction was the topmost concern in patients and second most important concern in caregivers [8].
All those patients may have some amount of baseline cognitive

Suggestions and Conclusion
Risk factors for neurocognitive dysfunction in hematological malignancies include high intensity cancer treatment, cranial radiation, female gender, co-existing neurologic problems, sleep deprivation, depression, fatigue, absence of social partner, HSCT, extensive chronic GVHD, use of corticosteroids, narcotics, and sedatives [35,[40][41][42][43]. Evaluation and documentation of neurocognitive deficits using standard neuropsychological battery of tests at baseline, during treatment, pre and post HSCT will help us gain more insight into the problem. This will allow us to recognize at-risk population and help us choose an optimal chemotherapy/conditioning regimen. For example, avoidance of total body/cranial irradiation or substitution of Busulfan for a TBI based conditioning regimen [44,45]. In patients with pre-existing seizure disorder, avoiding medications lowering seizure threshold will be useful. Careful assessment of need of narcotics, steroids and sedatives must be undertaken. Early recognition of CNS infections, PRES, TMA and optimum management of these will help mitigate some cognitive issues.
Cognitive rehabilitation measures for childhood leukemia survivors, school re-entry programs, psychosocial support, employment assistance, using an integrated approach to manage diet, sleep disorders and anxiety may also be beneficial [46][47][48]. To conclude, neurocognitive dysfunction in hematological malignancies can be a cause of serious morbidity. There is a need for validation and development of screening tests for neurocognitive dysfunction. Awareness about risk factors is needed to undertake timely interventions and to counsel patients about neurocognitive sequelae. Appropriate rehabilitation measures should be made available which will not only improve quality of life but also aid in achieving better overall outcomes.