Clinical study of chemotherapy-related cognitive impairment in patients with non-Hodgkin lymphoma

Abstract

BACKGROUND

Chemotherapy for malignant tumors can cause brain changes and cognitive impairment, leading to chemotherapy-induced cognitive impairment (CICI). Current research on CICI has focused on breast cancer and Hodgkin’s lymphoma. Whether patients with non-Hodgkin’s lymphoma (NHL) undergoing chemotherapy have cognitive impairment has not been fully investigated.

AIM

To investigate whether NHL patients undergoing chemotherapy had cognitive impairments.

METHODS

The study included 100 NHL patients who were required to complete a comprehensive psychological scale including the Brief Psychiatric Examination Scale (MMSE) at two time points: before chemotherapy and within 2 wk of two chemotherapy courses. A language proficiency test (VFT), Symbol Number Pattern Test (SDMT), Clock Drawing Test (CDT), Abbreviated Daily Cognition Scale (ECog-12), Prospective and Retrospective Memory Questionnaire, and Karnofsky Performance Status were used to assess cognitive changes before and after chemotherapy.

RESULTS

The VFT scores for before treatment (BT) and after treatment (AT) groups were 45.20 ± 15.62, and 42.30 ± 17.53, respectively (t -2.16, P < 0.05). The CDT scores were 8 (3.5-9.25) for BT and 7 (2.5-9) for AT groups (Z -2.1, P < 0.05). Retrospective memory scores were 13.5 (9-17) for BT and 15 (13-18) for AT (Z -3.7, P < 0.01). The prospective memory scores were 12.63 ± 3.61 for BT and 14.43 ± 4.32 for AT groups (t -4.97, P < 0.01). The ECog-12 scores were 1.71 (1.25-2.08) for BT and 1.79 (1.42-2.08) for AT groups (Z -2.84, P < 0.01). The SDMT and MMSE values did not show a significant difference between BT and AT groups.

CONCLUSION

Compared to the AT group, the BT group showed impaired language, memory, and subjective cognition, but objective cognition and execution were not significantly affected.

Key Words: Non-Hodgkin’s lymphoma, Hodgkin lymphoma, Lymphoma cognitive impairment, Chemotherapy-related cognitive impairment, Clinical study

Core Tip: The cognitive status of patients with non-Hodgkin’s lymphoma before and after chemotherapy was assessed using various cognitive scales. We observed chemotherapy-related cognitive impairment. Patients with non-Hodgkin’s lymphoma undergoing chemotherapy may experience chemotherapy-related cognitive impairment. The main manifestations were language, memory, and visuospatial dysfunction. Frontal lobe injury was more obvious, but no clear difference was observed in executive function.

INTRODUCTION

Lymphoma is a solid tumor that originates from the immune system and can occur at any age and in any part of the body. Its clinical manifestations vary; however, the typical presentation includes painless and gradually enlarging lymph nodes. It can also invade extranodal organs such as the nasopharynx, gastrointestinal tract, bone, and skin, leading to organ damage[1].

Lymphomas are divided into two major categories: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL). NHL is produced by T cells, B cells, NK cells, or histiocytes after antigen stimulation, and the tumor can also spread to the whole body, thus affecting organs throughout the body. NHL accounts for about 90% of all lymphomas and is one of the most common malignant tumors of the lymphopoietic system[2,3].

According to the 2015 global cancer statistics, there were over 380000 new cases of NHL worldwide in 2012 with the highest incidence in developed countries but a lower mortality rate compared to that in developing countries[4]. NHL ranked 8^th among new malignant tumors in men and 10^th among women, with over 180000 new cases in developed countries, and 7^th among men and 10^th among women, with over 200000 new cases in developing countries. Regarding deaths, NHL accounts for over 110000 male deaths worldwide, placing it 10^th among global causes of male cancer-related deaths, and 9^th among developing countries. However, it does not rank in the top 10 causes of male tumor-related deaths in the world or developed countries[5].

The rapid development of comprehensive cancer treatments has significantly improved the overall survival rate of cancer patients. With continuous improvements in treatment and economic levels, after standardized comprehensive treatment, the 5-year survival rate of most NHL patients can exceed 70%[6-8].

Previous studies have shown that chemotherapy for malignant tumors can cause brain changes and cognitive impairment, leading to chemotherapy-induced cognitive impairment (CICI). At present, CICI is often defined as a group of cognitive impairments occurring in tumor survivors during or after chemotherapy, including the ability to pay attention, memory, concentration, learning, understanding, language, judgment, reasoning, logical thinking, behavior, and execution[9,10].

Up to 75% of patients experience cognitive impairment during treatment and 35% experience cognitive impairment several years after treatment completion, which reduces the patient's quality of life[11,12].

Individuals with CICI often describe their cognitive problems as impaired memory and verbal fluency, slowed thought processes, and a shortened attention span. In some patients with breast cancer, cognitive impairment after chemotherapy manifests in speech and visuospatial abilities[13].

If left unmanaged, CICI can impair the performance of the individual at work and home and ultimately reduce the quality of life. CICI can also lead to long-term cognitive impairment. Some studies suggest that older patients with CICI have a 10%–15% chance of developing dementia per year, whereas patients without CICI have a probability of approximately 1%–2.5% per year[14-16]. Current research on CICI focuses on breast cancer and Hodgkin’s lymphoma[17,18]. Lymphoma is a solid tumor that can occur at any age and in any part of the body, and NHL accounts for about 90% of all lymphomas. Therefore, this study investigated whether NHL patients undergoing chemotherapy had cognitive impairment.

MATERIALS AND METHODS

This prospective study was approved by the ethics committee of Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine. Signed informed consent was obtained from all patients before inclusion in the study.

Patient recruitment and selection criteria

The patients were enrolled in the study based on specific inclusion and exclusion criteria. The inclusion criteria were as follows: (1) Pathological diagnosis of NHL; (2) Age 20 to 60 years; (3) Ability to provide informed consent; (4) No language barriers; and (5) Patients received standard chemotherapy regimens according to the NCCN guidelines. Exclusion criteria: (1) Current or previous diagnosis of brain tumor (primary or secondary); (2) Hydrocephalus, any type of dementia; (3) Mental disorders and other diseases that may affect cognitive function; (4) Life expectancy of less than 6 mo; (5) Current or past history of alcohol abuse; (6) Current or previous history of head trauma and brain surgery; (7) Hormone therapy (estrogen and progesterone compounds); (8) Active infection; (9) Thyroid disease; and (10) Underwent stem cell transplantation.

Study design

Participants were evaluated at two time points: Before treatment (BT) and 2 wk after two courses of chemotherapy [after treatment (AT)]. The evaluation included a complete comprehensive psychological assessment which comprised the Brief Psychiatric Examination Scale (MMSE), Verbal Fluency Test (VFT), Symbolic Number Pattern Test (SDMT), Clock Drawing Test (CDT), Simplified Daily Cognitive Scale (ECog-12) and Prospective and Retrospective Memory Questionnaire and Karnofsky Performance Status score.

Statistical analysis

Data analysis was performed using SPSS version 24.0, employing a two-tailed significance level of 0.05. A descriptive analysis was carried out for each item. The cytokine and psychological levels were analyzed before and after treatment. Mean ± standard deviation (SD) was used to describe normally distributed data, while non-normal distributed data were described by M (P25 and P75). A paired t-test was used for comparison.

RESULTS

A total of 100 NHL patients were included in this study. The demographic characteristics and clinical information of the participants are shown in Table 1. The median age of NHL patients in this study was 47 years, and the majority were between 43 years and 55 years. Of the participants, 49 were males (49%) and 51 females (51%). The median years of schooling was 7.5, predominantly ranging between 6 years and 8 years. According to the Ann Arbor staging system, 62 patients (62%) had stage II NHL, 26 (26%) had stage III, and 12 (12%) had stage IV NHL.

Table 1 Basic information for patients with non-Hodgkin’s lymphoma.

Clinical characteristics	Value
Age in yr	47 (43–55)
Sex
Male	49
Female	51
Education in yr	7.5 (6–8)
Ann Arbor stage
II stage	62
III stage	26
IV stage	12

Data are n or n (range).

The main results are shown in Table 2. The MMSE scores of the BT and AT groups were 27 (23.75–29), and 27 (23.25–29), respectively. After conducting the Wilcoxon rank-sum test on the relevant samples, the statistical value Z was -1.16 and P was 0.247, indicating that the difference was not statistically significant. The VFT scores of the BT group were 45.20 ± 15.62, and that of the AT group was 42.30 ± 17.53. Using a paired-sample t-test, the statistical t-value was 2.16, (P < 0.05), indicating a statistically significant difference. The SDMT scores were 24.5 (10.5–36) in the BT and 22.5 (12–33) in the AT groups. The Z was 0.69, (P -0.492), indicating that the differences were not statistically significant. The value of CDT in the BT group was 8 (3.5–9.25), and that in the AT group was 7 (2.5–9). The Z value was -2.1 (P < 0.05), suggesting a statistically significant difference. The retrospective memory (RM) values of the BT and AT groups were 13.5 (9–17) and 15 (13–18), respectively. The Z value was -3.7 (P < 0.01), and the difference was statistically significant. The prospective memory (PM) values of the BT and AT groups were 12.63 ± 3.61, and 14.43 ± 4.32 respectively. The t-value was -4.97 (P < 0.01), and the difference was statistically significant. The value of ECog-12 in the BT group was 1.71 (1.25–2.08), and that in the AT group was 1.79 (1.42–2.08). The Z was -2.84 (P < 0.01), and the difference was statistically significant.

Table 2 Comparison of cytokine and psychological tests before and after chemotherapy.

Parameter	BT group	AT group	t/Z value	P value
MMSE	27 (23.75–29)	27 (23.75–29)	-1.16	0.24
VFT	45.20 ± 15.62	42.30 ± 17.53	2.16	< 0.05
SDMT	24.5 (10.5–36)	22.5 (12–33)	0.69	0.49
CDT	8 (3.5–9.25)	7 (2.5–9)	-2.1	< 0.05
RM	13.5 (9–17)	15 (13–18)	-3.7	< 0.01
PM	12.63 ± 3.61	14.43 ± 4.32	-4.97	< 0.01
ECog-12	1.71 (1.25-2.08)	1.79 (1.42-2.08)	-2.84	< 0.01

Data are n (range) or mean ± standard deviation. AT: After treatment; BT: Before treatment; CDT: Clock Drawing Test; ECog-12: Abbreviated Daily Cognition Scale; PM: Prospective memory; RM: Retrospective memory; SDMT: Symbol Number Pattern Test; VFT: Verbal Fluency Test; MMSE: Brief Psychiatric Examination Scale (Mini-Mental State Examination).

DISCUSSION

Currently, there are many studies on cognitive impairment after chemotherapy, mostly focusing on breast and prostate cancers, whereas there are relatively few studies on NHL[19-21]. With the continuous improvement in NHL treatment, the survival period of patients is relatively long, emphasizing the need to address the quality of life of these patients. Therefore, it is imperative to study CICI in NHL patients.

It has been documented that lymphoma patients may have lower cognitive performance after chemotherapy, exhibiting poor performance in executive function and attention. Some patients also report severe fatigue and a significant decline in quality of life. Patients with chronic lymphocytic leukemia undergoing 3 mo of chemotherapy may experience impairment in executive function and memory[22]. In mouse experiments, chemotherapeutic drugs have been shown to impair memory for up to 12 h, passive avoidance learning, and new object recognition. Additionally, the cognitive performance of patients with breast cancer significantly differs at 1, 3, and 6 mo after chemotherapy compared to before chemotherapy, with a gradual decline in their cognitive ability[23]. Chemotherapy can also affect memory and damage processing speed, attention, and executive functions.

Most of the existing mechanisms revolve around the direct toxic effects of drugs on nerve cells, including the destruction of the blood-brain barrier, loss of neurons in the hippocampus, white matter damage, neuronal inflammatory damage, oxidative stress, etc[24,25]. However, the exact underlying mechanisms have not been fully elucidated. Endodermal injury plays a key role in the process of chemotherapy-related cognitive dysfunction. It was first reported that Bortezomib was involved in the inhibition of autophagic lysosome function of cerebral vascular endothelium through TFEB, which elucidates that cerebral vascular endothelium TFEB negatively regulates STAT3 transcription of IL23A. It was further demonstrated that IL23A, as a signaling molecule, is involved in the communication between endothelium and microglia, mediating microglia activation and synaptic phagocytosis[26].

In this study, we found that the VFT and CDT scores of NHL patients significantly decreased in the AT group compared to that of the BT group. Additionally, the scores of RM, PM, and ECog-12 significantly increased in the AT group. However, no significant differences were observed in MMSE and SDMT. The VFT scale is often used to evaluate instantaneous verbal memory, spontaneous verbal motor function, thinking organization, and interference inhibition abilities. The decreased scores in the AT group suggest impaired language function and frontal lobe damage in NHL patients after chemotherapy. The CDT score is often used to assess executive abilities by integrating tasks such as spatial organization, numerical order, and time comprehension. The decline in CDT scores in the AT group indicates impaired visuospatial ability in patients with NHL after chemotherapy mirroring the findings in the VFT score, which indicates frontal lobe dysfunction. The RM and PM scores reflect patient memory function. The increase in scores in the AT group indicates impaired retrospective and prospective memories in NHL patients after chemotherapy. The ECOG-12 scores indicate subjective cognitive changes. An increase in scores in the AT group indicated impaired subjective cognition in NHL patients.

Nevertheless, there was no significant change in the SDMT scores before and after chemotherapy, suggesting that patients did not experience chemotherapy-induced changes in visual processing, sensory functions, visuospatial abilities, or scanning movements. Moreover, there was no significant change in MMSE scores before and after chemotherapy, which could be related to the relatively short follow-up time in this study, leading to the lack of statistical difference in the MMSE score. Additionally, some studies have pointed out that MMSE may not be highly sensitive in detecting mild cognitive impairment.

CONCLUSION

In summary, compared with the BT group, the AT group showed impairments in language, memory, and subjective cognition, but objective cognition and executive performance were not significantly affected. This may be attributed to the fact that the second test was conducted within 2 wk after the two courses of chemotherapy, which might have resulted in only partial damage to cognitive functions. In this study, impairments were mainly observed in language, memory, and visuospatial abilities, with more noticeable frontal lobe injury, while no clear difference was found in executive function.