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ORIGINAL ARTICLE
Ahead of print publication  

Changes in glucose metabolism of the brain after immunochemotherapy in patients with diffuse large B-Cell lymphoma on fluorodeoxyglucose positron emission tomography/computed tomography


 Department of Nuclear Medicine, Faculty of Medicine, Training and Research Hospital, Recep Tayyip Erdogan University, Rize, Turkey

Date of Submission16-Jun-2022
Date of Acceptance07-Jul-2022
Date of Web Publication24-Aug-2022

Correspondence Address:
Ogün Bulbul,
Department of Nuclear Medicine, Faculty of Medicine, Training and Research Hospital, Recep Tayyip Erdogan University, Rize
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_37_22

  Abstract 

Objective: Mild cognitive impairment seen after chemotherapy is called chemo brain. Neuropsychological tests mainly diagnose chemo brain, but morphological or functional imaging modalities may also contribute to the diagnosis. This study aimed to examine the change in brain fluorodeoxyglucose (FDG) uptake after immunochemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). Materials and Methods: FDG positron emission tomography/computed tomography images performed for both staging and treatment response evaluation of patients treated with R-CHOP for DLBCL were retrospectively analyzed. It was investigated whether the FDG uptake of the brain decreased after the treatment. Results: There was no significant decrease in FDG uptake in the brain regions of 40 patients treated with R-CHOP compared to pretreatment. There was no significant change in brain FDG uptake after treatment between Ann Arbor Stage 1 or Stage 2 patients and Ann Arbor Stage 3 or Stage 4 patients compared to pretreatment. There was no significant change in brain FDG uptake after treatment compared to pretreatment between patients with Deauville score (DS) 1–3 and patients with DS 4 or 5 according to treatment responses. Patients with the most hypermetabolic lesion SUVmax >30.5 had significantly decreased posttreatment SUVmean in the right basal ganglia, left and right central regions, left cingulate and paracingulate cortices, right striatum, left and right frontal cortices, left occipital cortex, left and right parietal cortices, left and right precunei, and right temporal cortex. Conclusion: FDG uptake decreased in many brain regions after R-CHOP in patients with DLBCL whose lesions showed high FDG uptake.

Keywords: Chemotherapy-related cognitive impairment, diffuse large B-cell lymphoma, fluorodeoxyglucose F18, positron emission tomography/computed tomography



How to cite this URL:
Bulbul O, Göksel S, Nak D. Changes in glucose metabolism of the brain after immunochemotherapy in patients with diffuse large B-Cell lymphoma on fluorodeoxyglucose positron emission tomography/computed tomography. J Radiat Cancer Res [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.journalrcr.org/preprintarticle.asp?id=354442


  Introduction Top


Long-term effects of chemotherapy have gained importance in some malignancies due to the prolonged survival related to chemotherapy. One of the most important examples of these effects is mild cognitive impairment in breast cancer patients. This clinical condition characterized by decreased cognitive functions such as memory problems, learning problems, attention loss, and concentration loss is called chemo brain.[1] It has been revealed that oxidative stress, disruption of the blood–brain barrier, pro-inflammatory cytokines, DNA damage, insufficient repair of DNA, telomere shortening, hormonal changes, and neuronal genetic polymorphism can cause chemo brain.[1],[2]

The most critical points in oncological practice are progression-free survival, overall survival, and chemotherapy-associated fatal complications. Chemo brain is not a rare clinical situation. This clinical situation can make it difficult for patients to manage their daily activities and significantly reduce their quality of life.[3]

Cognitive functions are mainly evaluated by neuropsychological tests.[4] Functional imaging modalities such as functional magnetic resonance imaging and positron emission tomography/computed tomography (PET/CT) can reveal the effects of chemotherapy on brain metabolism.[4],[5] Our aim in this study is to examine the changes in the glucose metabolism of the brain in fluorodeoxyglucose (FDG) PET/CT imaging performed after immunochemotherapy (R-CHOP protocol [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone]) in patients with diffuse large B-cell lymphoma (DLBCL).


  Materials and Methods Top


The local ethics committee approved our study (Date: 18.05.2022, decision no: 2022/126). Due to the study's retrospective nature, the ethics committee waived the requirement for informed consent. This study was conducted in accordance with the Declaration of Helsinki principles.

Patient population

Patients diagnosed with DLBCL and were older than 18 years of age, who were treated with immunochemotherapy, and who underwent FDG PET/CT in our department between 2017 and 2022 for both staging and treatment response evaluation were identified. Patients who had a second malignancy, cerebral lymphoma involvement, whose brain images could not be evaluated due to motion artifact, and whose brain FDG uptake was lower than expected were excluded from the study. Finally, 40 patients were included in the study.

Positron emission tomography/computed tomography protocol and evaluation of images

After fasting for at least 6 h, FDG was administered intravenously at a 0.1 mCi/kg dose to patients whose blood glucose level was <200 mg/dl. Patients rested for 60 min in a dark, single room until imaging. PET/CT images were obtained from the vertex to the upper thigh as the imaging was performed for oncological purposes (Siemens Biograph mCT 20). First, nondiagnostic CT images were acquired using 120 kVp, 50 mAs, iodine-containing oral contrast, and free-breathing protocol. Then, PET images were obtained with a 2 min/bed position in three-dimensional mode. Brain images obtained from whole-body PET/CT images were evaluated using Siemens syngo.via VB30 MI Neurology software. Brain images were manually processed and brought into comparable geometry in axial, sagittal, and coronal planes with brain images of patients with similar demographic characteristics in the database [Figure 1] and [Figure 2]. SUVmean was calculated from basal ganglia, central region, cerebellum, cingulate and paracingulate cortex, corpus striatum, frontal lobe, mesial temporal region, occipital lobe, parietal lobe, precuneus, and temporal lobe areas with the help of software. In addition, the calculated SUVmean values were compared with the database, and standard deviation (SD) values were obtained. The parameters obtained from PET/CT before treatment and those obtained from PET/CT after treatment were compared.
Figure 1: (a) Coronal plane, (b) sagittal plane positron emission tomography images before manual processing; red arrow: The boundaries of the cerebral cortex of a normal individual in the database, green arrow: Boundaries of a patient's cerebral cortex

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Figure 2: (a) Coronal plane, (b) sagittal plane positron emission tomography images after manual processing

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Whole-body PET/CT images were evaluated on the Siemens syngo.via workstation. Ann Arbor stages of the patients were determined according to PET/CT performed during the staging phase,[6] and SUVmax of the most hypermetabolic lesion was measured. Patients with Ann Arbor Stage 1 and Stage 2 were considered the low stage group, while patients with Stage 3 and Stage 4 were considered the high stage group. In both the groups, pretreatment SUVmean and SD values of brain regions and post-treatment SUVmean and SD values were compared. Deauville scores (DS) were determined according to control PET/CT after immunochemotherapy.[7] The patients were divided into DS 1–3 and DS 4–5. The pretreatment SUVmean and SD values of the brain regions of both the groups were compared with the same parameters after treatment.

Statistical analysis

Statistical analysis of this study was performed using the SPSS 25 package program (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp). The conformity of the data to the normal distribution was evaluated with the Kolmogorov–Smirnov test. FDG uptake of brain regions before and after treatment was compared with “paired samples t-test” or “Wilcoxon test.” The changes in FDG uptake in the brain regions of the patients were divided into groups according to Ann Arbor stages and DS after treatment were compared using the “independent samples t-test” or the “Mann–Whitney U test”. P < 0.05 was considered statistically significant.


  Results Top


Detailed demographic information of the patients included in the study is given in [Table 1]. In the evaluation made on all patients, no significant difference was found in the glucose metabolism of any brain region before and after the treatment [Supplementary Table 1].[Additional file 1] No significant difference was found in the glucose metabolism of any region in the brain of patients with Ann Arbor Stage 1 or 2 and patients with Ann Arbor Stage 3 or 4 before and after treatment. According to treatment responses, in patients with DS 1–3 and DS 4, 5, no region was found that showed a significant decrease in brain glucose metabolism after treatment. The mean SUVmax of all patients' most hypermetabolic lesions associated with lymphoma was 30.5 ± 13.7. Patients with the most hypermetabolic lesion SUVmax >30.5 had significantly decreased posttreatment SUVmean values in the following brain regions: Right basal ganglia, left and right central regions, left cingulate and paracingulate cortices, right striatum, left and right frontal cortices, left occipital cortex, left and right parietal cortices, left and right precunei, and right temporal cortex.
Table 1: Detailed patient demographics

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  Discussion Top


Mild cognitive impairment after chemotherapy is a clinical condition that patients diagnosed with breast cancer frequently encounter and that seriously reduces their quality of life.[3],[4],[5],[8],[9] The R-CHOP immunochemotherapy protocol for the treatment of DLBCL provides prolonged survival.[10] Prolonged survival is the most critical goal of oncological treatments. Patients surviving longer are more likely to experience toxicities due to oncological treatments. Chemo brain is only one of the toxicities mentioned. Although the relationship between breast cancer treatment and chemo brain has been studied more in the literature, there are also studies showing the relationship between lymphoma treatment and chemo brain.[11],[12] Khan et al. showed that adult patients treated with four cycles of R-CHOP had lower Mini–Mental State Examination (MMSE) scores than those treated with four cycles of CHOP.[11] In the same study, patients treated with R-CHOP had higher levels of pro-inflammatory cytokines and thyroid-stimulating hormone and lower levels of T3 and T4 hormones. It has been hypothesized that pro-inflammatory cytokines decrease cognitive functions. Zimmer et al. reported that cognitive functions were lower in patients with B-cell non-Hodgkin lymphoma treated with the R-CHOP protocol compared to the control group.[12] In addition, it was shown in this study that the combination of bendamustine and rituximab decreased cognitive functions more than the R-CHOP protocol. Baudino et al. investigated the long-term effects of chemotherapy on cognitive functions and the effect of chemotherapy on brain glucose metabolism in patients with lymphoma.[13] Of the 50 patients included in the study, 32 received chemotherapy, and 18 did not. Of 32 patients who received chemotherapy, 22 had non-Hodgkin lymphoma, 10 had Hodgkin lymphoma, and 22 of these 32 patients had rituximab in their chemotherapy protocol. FDG uptakes and neuropsychological test results of the brain regions of 18 patients who did not receive chemotherapy, FDG uptakes of brain regions in PET/CT performed after the end of treatment in 32 patients who received chemotherapy, and neuropsychological test results of these patients were evaluated. A significant difference was found between the MMSE scores and the Trail Making Test-B results of the patients who received chemotherapy and the same test results of those who did not receive chemotherapy. The voxel-based evaluation determined that FDG uptake was lower in voxels containing the anterior cingulate cortex and frontal cortex in patients who received chemotherapy than in patients who did not. Our study found no difference in FDG uptakes of brain regions before and after treatment in 40 adult patients with DLBCL treated with the R-CHOP protocol. However, in the subgroup analysis, patients with SUVmax of the most hypermetabolic lesion associated with lymphoma higher than 30.5 had lower FDG uptake in many brain regions after treatment. We thought the possible reason for this might be that the high FDG uptake in the lymphoma-related lesion may be associated with aggressive tumor biology and/or high inflammation in the lesion. Accordingly, increased pro-inflammatory cytokines may have decreased glucose metabolism in many brain regions. According to this hypothesis, brain FDG uptake may decrease significantly with treatment in patients with high Ann Arbor stage and patients with high DS after treatment, possibly due to high pro-inflammatory cytokines. However, the results of our study showed that the Ann Arbor stage and the DS were not associated with decreased FDG uptake in the brain. The possible reason for this is the small number of patients.

Other limitations in our study are lack of clinical examination of the patients for mild cognitive impairment, lack of pretreatment and posttreatment neuropsychological tests, lack of specific PET/CT imaging of the brain region, and inability to correlate FDG uptake of the lymphoma-associated lesion with systemic inflammation because pro-inflammatory cytokines were not measured.


  Conclusion Top


In our study, we concluded that FDG uptake decreased in many brain regions after immunochemotherapy in patients with DLBCL whose lesions showed high FDG uptake. Confirmation of this result is important and necessary in studies with higher patient numbers using specific brain FDG PET/CT imaging.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Ren X, Boriero D, Chaiswing L, Bondada S, St Clair DK, Butterfield DA. BBA-Molecular Basis of Disease Plausible biochemical mechanisms of chemotherapy-induced cognitive impairment (” chemobrain “), a condition that signi fi cantly impairs the quality of life of many cancer survivors. Biochim Biophys Acta Mol Basis Dis 2019;1865:1088-97.  Back to cited text no. 1
    
2.
Wardill HR, Mander KA, Van Sebille YZ, Gibson RJ, Logan RM, Bowen JM, et al. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. Int J Cancer 2016;139:2635-45.  Back to cited text no. 2
    
3.
Selamat MH, Loh SY, Mackenzie L, Vardy J. Chemobrain experienced by breast cancer survivors: A meta-ethnography study investigating research and care implications. PLoS One 2014;9:e108002.  Back to cited text no. 3
    
4.
Marín AP, Sánchez AR, Arranz EE, Auñón PZ, Barón MG. Adjuvant chemotherapy for breast cancer and cognitive impairment. South Med J 2009;102:929-34.  Back to cited text no. 4
    
5.
Matsuda T, Takayama T, Tashiro M, Nakamura Y, Ohashi Y, Shimozuma K. Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients-Evaluation of appropriate research design and methodology to measure symptoms. Breast Cancer 2005;12:279-87.  Back to cited text no. 5
    
6.
Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989;7:1630-6.  Back to cited text no. 6
    
7.
Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the first ınternational workshop on ınterim-PET-scan in lymphoma. Leuk Lymphoma 2009;50:1257-60.  Back to cited text no. 7
    
8.
Castellon SA, Ganz PA, Bower JE, Petersen L, Abraham L, Greendale GA. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol 2004;26:955-69.  Back to cited text no. 8
    
9.
Breckenridge LM, Bruns GL, Todd BL, Feuerstein M. Cognitive limitations associated with tamoxifen and aromatase inhibitors in employed breast cancer survivors. Psychooncology 2012;21:43-53.  Back to cited text no. 9
    
10.
Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the groupe d'etude des lymphomes de l'adulte. J Clin Oncol 2005;23:4117-26.  Back to cited text no. 10
    
11.
Khan MA, Garg K, Bhurani D, Agarwal NB. Early manifestation of mild cognitive impairment in B-cell non-Hodgkin's lymphoma patients receiving CHOP and rituximab-CHOP chemotherapy. Naunyn Schmiedebergs Arch Pharmacol 2016;389:1253-65.  Back to cited text no. 11
    
12.
Zimmer P, Mierau A, Bloch W, Strüder HK, Hülsdünker T, Schenk A, et al. Post-chemotherapy cognitive impairment in patients with B-cell non-Hodgkin lymphoma: A first comprehensive approach to determine cognitive impairments after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone or rituximab a. Leuk Lymphoma 2015;56:347-52.  Back to cited text no. 12
    
13.
Baudino B, D'agata F, Caroppo P, Castellano G, Cauda S, Manfredi M, et al. The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients. Q J Nucl Med Mol Imaging 2012;56:559-68.  Back to cited text no. 13
    


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