Chemotherapy (CT) is the cornerstone therapy for almost all hematological malignancies. Advances in CT protocols with better supportive care and earlier detection of its toxicity will lead to an increase in the number of patients undergoing complete remission with the least toxicity [10].
However, the chemotherapy intake is often accompanied by many side effects involving immunosuppression, myelosuppression, gastrointestinal distress, anemia, hair loss, secondary neoplasm, infertility, teratogenicity, peripheral neuropathy, cognitive impairment, tumor lysis syndrome, and organ damage [4].
Some cognitive problems in those who receive chemotherapy are more severe than in those who only receive locoregional therapy (e.g., radiation, surgery), and it can negatively impact activities of daily living [8, 11].
Most of the previous studies were targeting the correlation between chemotherapy protocol intake and the cognitive functions without considering the other variable factors. Also, few of the previous studies concerning with CICI were targeting hematological malignancies in specific. That is why we had targeted our study for the discussion of the correlation between cognitive impairment following chemotherapy intake among hematological malignancy patients with multiple factors including the nature of disease, type of chemotherapy regimen, number of its cycles, duration of hospital stay, age of the patient, sex, route of administration of the chemotherapy, remission status of patients, and other comorbidities (hypertension, diabetes, and viral hepatic infections).
In our study, 93 patients (62%) developed various degrees of cognitive impairment, and 57 patients (38%) had proven to have normal cognitive functions; this is in accordance with literature which suggests that chemotherapy has a negative impact on cognitive functioning [12, 13]. Some potential mechanisms of CICI include the following: direct neurotoxic injury to neurons, white or gray matter microvasculature that causes direct ischemia, altered levels of neurotransmitters or DNA damage, and subsequent oxidative stress [5].
Although several positive studies have found evidence supporting the influence of chemotherapy on cognitive functioning [1, 14,15,16,17], yet other negative studies have also been reported [18,19,20]; this discrepancy may be due to one or more of other variable factors as reported by Vardy et al. This included the different chemotherapy regimens administered, variations in normative data and reference groups, difference in tools, and scales used for cognitive impairment diagnosis [21]. Moreover, Peckham reported that cognitive dysfunction due to chemotherapy may not appear immediately after treatment but needs at least from 2 to 3 years after treatment cessation [22, 23].
In this study, we assessed the impact of age on the cognition functions and we found a statistically significant impact of aging on the cognitive functions (p value < .001) that severely affect all cognitive components except naming and orientation. This is in agreement with Loh et al. who reported that advancing age is a known risk factor for cognitive impairment; the investigations of the biological mechanics of CICI in older patient are more complex than in younger patients for several reasons: (1) many mechanisms that are involved in CICI are also involved in comorbid precondition, (2) comorbid conditions can increase vulnerability to CICI by biological mechanisms similar or dissimilar from the mechanisms causing the condition itself, and (3) the use of multiple medications in elderly augments the great undesired CICI [24].
Concerning the effect of premedication comorbidities like hypertension, diabetes, and viral hepatic infections, our study results had shown a statistically significant impact of comorbidities on the cognitive functions (p value < 0.001), with a greater affection on abstraction and delayed recall. This is in agreement with other previous studies, which considered comorbidity’s impact on cognitive functioning irrespective of the cancer diagnosis [25]. Also, Panza et al. is coming in agreement with our results [26].
So careful measurement and assessment of comorbid conditions are particularly important to consider in pretreatment assessment in cancer patients—as the same cytokines and cognate receptors implicated in these diseases are also implicated in CICI [27].
As regards the sex of the patient, our study result did not find an appreciable impact of sex on neurocognitive ability; however, female patients had statistically significant impairment in naming function than male (p value 0.009). Also, some studies in pediatric group found that girls perform more poorly than boys in assessment of cognitive function tests [28]; this may be explained by sex-based differences in white matter development [29]. On the other hand, males tend to perform better in visuospatial and motor tasks, whereas females tend to perform better in certain verbal areas [30].
In our study, we highlighted the impact of each type of hematological malignancy (ALL, AML, CML, CLL, myeloma, lymphoma, and MDS) among chemotherapeutic treated patients on the cognitive functions. We found that there is a statistically significant impact of type of the malignancy on the cognitive functions (p value 0.21), as all patients with MDS suffered from cognitive impairment, especially executive functions (p value < 0.001), followed by the abstraction (p value 0.012). Our result in accordance with one cogitation of patient role with MDS or AML patient reported increased cognitive deficits prior to any handling and more dysfunction up to 1 month after therapy; this may be related to the point of circulating cytokine [31]. Another study of patients with MDS and CML reported high pace of impairment at baseline and improvement up to 18 months after treatment [32]. We recommend more subject areas with larger number of patients of each disease for accurate judgment.
In our study, we found that the number of chemotherapy cycles that had been received by patients had statistically significant impact on naming and orientation cognitive function (p value 0.029 and 0.022, respectively), patients who received Velcade chemotherapy had statistically significant lower executive and abstraction function.
This is in accordance with Jones et al. who found that many myeloma patients are likely to suffer impaired cognitive function after their initial multiple myeloma therapy. The patients had received a median of 3 to 4 cycles of induction therapy with Velcade-based induction therapy, and stem cell transplantation often causes further impairment. The most common signs of cognitive impairment were problems with learning, memory, and coordination [33].
The period of hospital stay is another point which had been discussed in our study, and we found that there is no statistically significant difference between it and the CICI except on abstraction dysfunction (p value 0.003). In contrast, Loh et al. found that long-term hospitalization may increase and worsen the cognitive impairment as it affects the quality of life of the patients in general. Thus, much more studies with longer period of follow-up are needed [34].
When comparing between the effect of oral and parenteral routes of chemotherapy on cognition functions, we found a significant difference being more with parenteral route (p value 0.16) with highly significant defect in executive part (p value < 0.001). However, most studies stress that drugs that can cross BBB (e.g., methotrexate or 5-fluorouracil) has more detrimental effects on cognition function. It was suggested that cytokines play a dominant role in the neuro-immuno-endocrine processes induced by cancer cells and cytotoxic chemotherapy. Chemotherapeutic agents, which are mostly unable to hybridize the blood-brain barrier (BBB) due to their molecular size, can cause toxicity to the brain indirectly via the pro-inflammatory cytokine pathways. It also was suggested that the accumulation of a combination of drug, rather than some drugs, may enhance the neurotoxicity in cancer patient.
Another point of study was the follow-up assessment after 6 months, and its impingement on chemotherapy-induced cognitive handicap revealed no statistically significant divergence. However, some other studies uncovered that deteriorated cognitive affair in children with cancer could be attributed either to cancer treatments including chemotherapy or to cancer per se as some patients who did not achieve remission had poorer cognitive function [35]; this controversy may be explained by relatively short stop of the study and in need for wide scale of patients. So, further larger, prospective, long-term studies are necessary to definitively assess this impairment.
To summarize, there is a necessary need of more comprehensive neuropsychological tests for specific information about the nature and severity of intellectual dysfunction at different times throughout the distance of the discourse full point and even for long terminus survivors as a second step to provide an improved scene for specific effect related to cognitive dysfunction in patients with hematological malignancies. Besides, studies on big sample distribution are also advised to clarify the role of predisposing variables.
Furthermore, the growth of interference that addresses cognitive late answer is imperative, and intervention studies can be more successfully created to target the actual mechanisms to try and prevent cognitive impairment from occurring and address it once it has happened.
