Changes in chemotherapy-induced cognitive impairment in gastrointestinal cancer survivors using multidomain assessments: a prospective cohort study

Changes in chemotherapy-induced cognitive impairment in gastrointestinal cancer survivors using multidomain assessments: a prospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Changes in chemotherapy-induced cognitive impairment in gastrointestinal cancer survivors using multidomain assessments: a prospective cohort study Kazuya Saita, Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Fumiko Kaneko, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5191114/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Feb, 2025 Read the published version in Journal of Cancer Survivorship → Version 1 posted 8 You are reading this latest preprint version Abstract Purpose: Risk factors for cancer-related cognitive impairment (CRCI) are diverse; neuroimaging instruments are recommended to complement subjective and objective cognitive assessments. This study aimed to evaluate the feasibility of a multidomain assessment protocol for CRCI in gastrointestinal cancer survivors. Methods: Twenty-four patients with gastrointestinal cancer scheduled for chemotherapy and 24 healthy controls were recruited. The Functional Assessment of Cancer Therapy-cognitive function (FACT-Cog) was used to assess subjective cognitive functions. Objective cognitive function was assessed using the trail-making test, auditory verbal learning test (AVLT), and verbal fluency test. Cerebral hemodynamic changes in the prefrontal cortex were measured using portable functional near-infrared spectroscopy (P-NIRS). Assessments were conducted at baseline and six-month follow-up. Results: Thirty-eight participants were included in the analysis. There was a statistically significant difference in AVLT-delayed recall (p=0.002) in the chemotherapy group compared with the healthy control group, but no significant difference in either group for other cognitive assessments. The chemotherapy group exhibited reduced activity in the left frontal pole at six months post-treatment compared to baseline (p=0.018). Conclusions: Gastrointestinal cancer survivors who receive chemotherapy may exhibit poorer delayed recall of memory functions than healthy individuals. Monitoring prefrontal cortical hemodynamics using P-NIRS during cognitive tasks is feasible for clinical application and understanding CRCI symptoms. Implications for Cancer Survivors : This multidomain assessments ars translatable to clinical practice and useful for other cancers. Furthermore, It can lead to a deeper understanding of the impact of depressive symptoms and declining motivation on the cognitive function of cancer survivors. Cancer related cognitive impairment prefrontal cortex neuroimaging cognitive function near-infrared spectroscopy Figures Figure 1 Figure 2 Introduction The number of cancer cases continues to increase worldwide, and the number of cancer survivors has increased owing to advances in technology and early detection of cancer. One problem with cancer survivorship care is cancer-related cognitive impairment (CRCI) [ 1 ]. Chemotherapy-induced cognitive dysfunction is a major impairment experienced by cancer survivors during the treatment process and is also known as “ Chemobrain ” [ 2 , 3 ]. The degree of impairment in CRCI is similar to that in mild cognitive disorders. Specific cognitive domains include attention, processing speed, memory, and executive function. Several factors are thought to be associated with the occurrence of CRCI, including the cancer itself, effects of cancer treatment (e.g., chemotherapy, hormone therapy), co-occurring symptoms (e.g., fatigue, distress), genetic factors (e.g., APOE-4), physiological factors (e.g., dysregulation of inflammatory cytokines, disruption of the blood-brain barrier), and sociodemographic factors (age, education level) [ 4 , 5 ]. These factors complicate our understanding of CRCI symptoms. The recommendations of the International Cognition and Cancer Task Force (ICCTF) include several statements for study designs to capture CRCI: 1) longitudinal studies that include pre- and post-treatment, 2) disease-specific and healthy control groups, and 3) neuroimaging data for objective and subjective assessment [ 6 ]. Regarding assessment methods for CRCI, the ICCTF has recommended the following neuropsychological assessments (NPTs): the Trail Making Test (TMT), Hopkins Verbal Learning Test-Revised, and Controlled Oral Word Association Test (COWA) [ 7 ]. Nevertheless, 10 years after their advocacy, these recommended assessments are not being used worldwide for CRCI assessment, and a consensus is yet to be established [ 8 ]. This may be because although NPTs are relatively widespread worldwide, the assessments are language-mediated and have not been standardized in minority language-speaking countries. As similar verbal memory and word fluency tests exist in all countries, reports from minority-language countries are necessary to understand the incidence of CRCI. On the other hand, patient-reported outcomes (PROs) as subjective assessments are also sensitive for CRCI detection. The Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) version 3 is the most frequently used international assessment of PRO assessing CRCI [ 8 ]. In addition to these cognitive assessments, neurophysiological biomarkers measuring brain activity are recommended as adjunct diagnostic tools. Several neuroimaging devices are used to measure brain activity, and functional magnetic resonance imaging (fMRI) is a representative device. However, given its clinical application, applying fMRI to all non-central nervous system cancers is not feasible from an economic and time-effective perspective. Functional near-infrared spectroscopy (fNIRS) is a noninvasive neuroimaging method that addresses this problem. fNIRS measures changes in cerebral blood flow associated with neural activity based on the neurovascular coupling (NVC) response. The fNIRS device is expected to bridge the gap between NPT and PRO as an adjunct diagnostic tool for current cognitive function assessment [ 9 , 10 ]. In this study, we applied portable fNIRS (P-NIRS), which is less restraining and burdensome to patients and can be used under conditions similar to those in daily life. To our knowledge, only one study has reported the clinical application of fNIRS measurements in addition to NPT and PRO to detect CRCI in breast cancer [ 11 ], and none has reported on the use of the P-NIRS device in gastrointestinal cancer. This study aimed to prospectively investigate neurocognitive changes in gastrointestinal cancer survivors before and after chemotherapy using a multidomain assessment and compare them with healthy volunteers. To capture neurocognitive changes from multiple perspectives, the secondary aim was to investigate the feasibility of clinical applications for measuring cortical hemodynamic changes based on NVC responses as an additional diagnostic tool in conjunction with cognitive functional assessments. Materials and Methods Study design and participants This study prospectively recruited 48 volunteers to enroll between September 2022 and December 2023, 24 each in the cancer chemotherapy (C+) and healthy control (HC) groups. Each participant was enrolled after eligibility checks with written consent after providing informed consent for the study. Measurements were completed before chemotherapy or baseline assessments and then after six-month follow-up assessments and were evaluated under the same environmental conditions. Based on previous neuroimaging studies [ 12 , 13 ], we estimated the feasible number of participants from previous outpatients at our single institution and decided on a sample size of 40: 20 in the C + group and 20 in the age- and sex-matched HC group. Assuming a dropout rate of 10%, a total of 48 cases were included in this study. This study was approved by the Ethical Review Committee for Epidemiological Research of Hiroshima University (E2022-0061). The C + group included outpatients at the Hiroshima University Hospital who were to begin their first course of chemotherapy following a diagnosis of gastrointestinal cancer (colorectal, gastric, or esophageal cancer). The HC group recruited healthy volunteers without cancer or central diseases from staff or family members of patients in outpatient rehabilitation facilities and community centers in the same residential area. The inclusion criteria for the C + group were as follows: 1) individuals who were at least 20 years and < 85 years old, 2) individuals who met the diagnostic criteria for gastrointestinal cancer (colorectal cancer, gastric cancer, esophageal cancer), 3) individuals who were scheduled to start the first course of chemotherapy treatment, 4) individuals with no anemic symptoms and a hemoglobin level of > 8.0 g/dl on a blood test, 5) individuals with an Eastern Cooperative Oncology Group- performance status score (ECOG-PS) of 0 or 1, 6) individuals whose first language is Japanese, 7) individuals scheduled for outpatient visits for at least six-months, and 8) individuals who provided written consent to participate in this study. The exclusion criteria were as follows: 1) individuals with a history of chemotherapy treatment for cancer, 2) individuals with a diagnosis of dementia or cognitive decline equivalent to dementia (Mini-Mental State Examination, Japanese version, less than 24 points), 3) individuals with a diagnosis of severe depression or psychiatric disorder, 4) individuals regularly using sleeping pills due to sleep disorders, 5) individuals with primary brain tumors, metastases or disorders to the central nervous system, 6) individuals with a history of alcohol or drug addiction, 7) individuals with a history of opioid analgesic use due to cancer pain, 8) individuals with cachexia or other poor systemic conditions, 9) individuals with serious liver disease, renal disease, seizure disorder, cardiac complications, 10) pregnant and lactating women, and 11) other individuals judged to be inappropriate by the principal investigator. It was planned to exclude from the analysis cases where follow-up data could not be obtained due to an individual's unanticipated life events or individual intent. Individuals for whom follow-up data were not available due to an unforeseen life events were planned to be excluded from the analysis. Assessments and fNIRS measurements During the eligibility check, the following information was collected from the individuals as sociodemographic factors related to cognitive function: age, sex, education level, marital status, and employment status. Clinical characteristics, including tumor stage, cancer site, line of therapy, and chemotherapy regimens, were collected from the electronic medical records at our facility. In both groups, the Mini-Mental State Examination, Japanese version, and the Japanese Adult Reading Test were used to assess cognitive functional screening and predict IQ as a cognitive reserve at baseline. In the C + group, the co-occurring symptoms of cancer-related fatigue, sleep disturbances, and pain were investigated through self-reporting; anemia was screened based on blood hemoglobin levels. FACT-Cog version 3 was used to assess subjective cognitive complaints. The FACT-Cog is a 37-item, 5-point questionnaire that assesses perceived cognitive decline and recommends the use of sub-items rather than the total score, as it is divided into four sub-items. The study used scores for perceived cognitive impairments (CogPCI: score range 0–72) and perceived cognitive abilities (CogPCA: score range, 0–28). The Japanese versions of the TMT (TMT-J), Rey auditory verbal learning test (AVLT), and verbal fluency test (VFT) were used to evaluate objective cognitive function. The performance time of the TMT-J was assessed for part A (a task to connect numbers in sequence) to measure the processing speed domain and part B (a task to connect numbers and letters alternately) to measure the executive function domain. The AVLT was used to assess the verbal memory domain, and the following main outcome measures were assessed: total number of words from the first to fifth (AVLT-sum) and number of delayed recalls (AVLT-DR/AVLT-7). A letter fluency task was selected for the VFT to assess the language and executive function domains. The total number of 3 mora generated per 60 s was recorded according to COWA, and the number of generated words and duplicate errors for each mora (/a/ /ka/ /shi/) were recorded. Continuous-wave P-NIRS (HOT-2000, NeU Corporation, Tokyo, Japan) is a wireless device with a Bluetooth connection. The sampling rate was 10 Hz, and the wavelength of the near-infrared light was 810 nm. This device allows the measurement of changes in total hemoglobin (THb) concentration according to the modified Beer–Lambert law; the reliability of prefrontal cortex measurements compared to multichannel fNIRS has been demonstrated by prior P-NIRS devices [ 14 ]. The NVC response is the principle of fNIRS measurements, and THb is one of the representative indicators of fNIRS, which represents the sum of oxyhemoglobin (O 2 Hb) and deoxyhemoglobin (HHb) concentrations. In a typical NVC reaction, THb and O 2 Hb concentrations increase if HHb remains unchanged. The P-NIRS instrument incorporates a multi-distance optodesis method [ 15 ] that removes the skin blood flow component by implementing a short channel to compensate for the shortcomings of previous NIRS studies [ 16 ]. Based on the International 10–20 method, the positions of the left and right channels were defined as the positions corresponding to the frontal pole (FP) on the Fp1 and Fp2 lines or the lateral region (corresponding to part of the ventral and dorsal prefrontal cortex) as the lateral prefrontal cortex (LPFC). The participants in the P-NIRS experiment were seated in a quiet environment. The experiment used a block design method, and the most commonly used letter fluency task was the cognitive task for the fNIRS experiment. Based on previous studies [ 17 ], a modified protocol was used, in which, after an initial 30-s rest period, a 120-s cycle consisting of a 30-s control task, a 60-s phonemic fluency task, and a 30-s recovery task was repeated three times. The control task consisted of repeated vocalizations of the Japanese vowels (/a/, /i/, /u/, /e/, and /o/). The VFT comprised two sets of three 60-s repetitions of one mora as a phonemic fluency task (/shi/, /i/, /re/, or /a/, /fu/, /ni/). Analysis Representative values for sociodemographic data, clinical characteristics, and cognitive functional assessment are expressed as means or medians, depending on the skewness of the distribution of the descriptive data. The Shapiro–Wilk test was used to test for normality. To compare the baseline characteristics and clinical data between the groups, we used the two-sample t-test or Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables. Several parameters of the objective cognitive assessment using NPTs were transformed into age-matched normalized scores (Z-score) based on previous studies to obtain consistent descriptive data [ 18 – 20 ]. The TMT-A, TMT-B, and VFT-error were flipped values of the Z-score used so that the positive direction of cognitive performance had a better score. Welch’s two-sample t-test was used to compare differences in changes between the groups in each cognitive function assessment. Missing data without follow-up assessments were excluded. To compare within-group data, the paired t-test or Wilcoxon signed-rank test was used. To calculate the percentage of CRCI incidence, PRO and NPT were based on the following methods: for NPT, the ICCTF-recommended criteria for CRCI were used, defined as ≥ ± 1.5 SD of the standard for two NPTs or ≥ ± 2.0 SD for one NPT [ 7 ]; for PRO by FACT-Cog, the clinically important difference in FACT-Cog was defined as subscale scores ranging from 6.4 to 10.3%, so we defined this as a decrease of at least 4.6 points (6.4% decrease) on the CogPCI score or at least 1.8 points (6.4% decrease) on the CogPCA [ 21 ]. For the fNIRS analysis, pre-processing of the raw data was performed using the statistical analysis software TOMATO (HOT-ANALYSIS; NeU Corporation, Tokyo, Japan). A median filter and moving average were used for noise reduction. First, the median filter was set to a time window of 1 s to reduce the spike noise caused by body movement. Subsequently, the moving average was set to 3 s to smoothen the waveform data. The smoothed waveform data were averaged, and a baseline correction was performed with the task start time set to zero. To allow for inter-channel and inter-subject comparisons, we converted the Z-score to represent the change in THb concentration. It was converted to a normalized averaging waveform by dividing by the standard deviation of the 20 s value of the control task. Matlab R 2023a (Mathworks, Inc., Natick, MA, USA) was used to analyze the fNIRS data after pre-processing. Linear mixed models were used for between-group and within-group comparisons of the fNIRS data. The fixed effects were group (C + and HC groups), period (baseline and follow-up), and task condition (control task and VFT task), whereas the random effects were individual participants. The two-sided significance level was set at 5%. All statistical analyses were performed using JMP pro 17.0.0 (SAS Institute Inc., Cary, NC, USA). Results After eligibility checks, 48 participants (24 volunteers each in the C + and HC groups) were enrolled, and 38 participants (19 in each group; median age, 74 years; 12 men and 7 women, respectively) were finally included in this study. Of the five individuals in the C + group who dropped out, four died, and one was difficult to follow up due to outpatient treatment outside the prefecture. Of the five individuals in the HC group who dropped out, two had surgery due to orthopedical conditions, and two were hospitalized due to cardiac and cerebrovascular diseases and, therefore, could not undergo follow-up assessments. The other did not wish to be followed up due to the bereavement of a family member. Baseline socio-demographics and clinical characteristics are presented in Table 1 and Table 2 . Table 1 Between-group comparisons of socio-demographic characteristics and cognitive assessments at baseline Total (N = 38) mean [95%CI] C + group (N = 19) mean [95%CI] HC group (N = 19) mean [95%CI] p-value Socio-demographic characteristics Age median (IQR) 74 (64-79.25) 74 (67–77) 74 (49–80) 0.977 b Gender men (%) women (%) 24 (63.2) 14 (36.8) 12 (63.2) 7 (36.8) 12 (63.2) 7 (36.8) 1.000 c Race/Ethnicity Asian/Japanese (%) 38 (100.0) 19 (100.0) 19 (100.0) 1.000 c Education level high school (12 ≧) (%) college (12 <) (%) 23 (60.5) 15 (39.5) 13 (68.4) 6 (31.6) 10 (52.6) 9 (47.4) 0.319 c Marital status single (%) married (%) 5 (13.2) 33 (86.8) 3 (15.8) 16 (84.2) 2 (10.5) 17 (89.5) 0.631 c Employment status unemployed (%) being employed (%) 22 (57.9) 16 (42.1) 14 (73.7) 5 (26.3) 8 (42.1) 11 (57.9) 0.049 c* Objective cognitive assessments MMSE , score, median (IQR) 30 (28–30) 30 (29–30) 30 (28–30) 0.772 b JART , FSIQ 102.58 [99.11, 105.89] 100.21 [94.98, 105.45] 104.79 [100.23, 109.35] 0.175 a TMT-A , sec, median (IQR) 47 (33-63.25) 43 (33–74) 51 (34–59) 0.759 b TMT-B , sec, median (IQR) 76.5 (60.5–103) 78 (59–119) 75 (67–98) 0.781 b AVLT-sum , words 38.92 [35.55–42.29] 37.11 [32.07, 42.14] 40.74 [35.93, 45.55] 0.281 a AVLT-DR , words 7.58 [6.51, 8.65] 7.32 [5.65, 8.99] 7.84 [6.36, 9.33] 0.624 a VFT-sum , words 32.84 [29.09, 36.60] 32.89 [27.83, 37.96) 32.79 [26.74, 38.84] 0.978 a VFT-error , words 1.97 [1.27, 2.68] 2.42 [1.59, 2.42] 1.52 [0.34, 2.71] 0.202 a Subjective cognitive assessments, FACT-Cog Cog PCI , score, median (IQR) 65.5 (60.5–70) 66 (59–70) 65 (61–68) 0.568 b Cog PCA , score, median (IQR) 23 (22–25) 24 (22–26) 23 (22–25) 0.385 b AVLT-DR, (Rey) Auditory Verbal Learning Test - delayed recall (Trial 7); AVLT-sum, (Rey) Auditory Verbal Learning Test - sum (Trial 1–5); C + group, Cancer chemotherapy group; CI, confidence interval; Cog-PCA, cognitive function – perceived cognitive ability; Cog-PCI, cognitive function – perceived cognitive impairment; FACT-Cog, Functional Assessment of Cancer Therapy - Cognitive Function; FSIQ, Full-scale intelligence quotient; HC group, healthy control group; IQR, Interquartile range; JART, Japanese Adult Reading Test; MMSE, Mini-Mental State Examination; TMT-A, Trail Making Test- part A; TMT-B, Trail Making Test - part B; VFT-sum, Verbal (Phenomic) Fluency Test - total cumulative number for three mora, VFT-error, Verbal (Phenomic) Fluency Test - number of repeated errors for the three mora a, two sample t-test; b, Wilcoxon rank sum test; c, square-test; *p < 0.05 Table 2 Clinical characteristics in the cancer chemothrapy group T0 T1 Tumor stage Ⅰ Ⅱ Ⅲ Ⅳ 2 3 7 7 Cancer sites Colorectum Stomach Oesophagus 5 5 9 Line of therapy Adjuvant chemotherapy Neoadjuvant chemotherapy Chemotherapy Chemoradiation 8 5 5 1 Chemotherapy regimen DCF CAPOX SOX + HER SOX + NIVO NIVO + IPI S-1 CF CF + NIVO 5 5 2 2 2 1 1 1 Hemoglobin level g/dl (SD) [95%CI] 12.31 (1.80) [11.44–13.18] 11.74 (1.53) [10.97–12.50] Co-occurring symptoms Fatigue (%) Sleep disturbance (%) Pain (%) 1 (5.2) 0 (0) 0 (0) 7 (36.8) 4 (21.1) 1 (5.2) CAPOX, capecitabine + oxaliplatin; CF, cisplatin + 5-FU; CI, confidence interval; DCF, docetaxel + cisplatin + 5-FU; HER, trastuzumab; IPI, Ipilimumab; NIVO, nivolumab; SD, standard deviation; SOX, S-1 + oxaliplatin Comparisons between the C + and HC groups at the baseline cognitive functional assessment showed no statistically significant difference in PRO and NPT scores (Table 1 ; Supplementary Table 1). The change in PRO and NPT between groups was not significantly different in the ΔCogPCI or ΔCogPCA scores on the FACT-Cog (Fig. 1 A). A comparison of the NPT between the groups showed a statistically significant difference (t = 3.365, p = 0.002, d = 1.092) in the ΔAVLT-DR but no statistically significant change in the other NPT scores (Fig. 1 B; Supplementary Table 2). As shown in Supplementary Fig. 1, the NPT scores showed an overall trend toward lower cognitive performance in the C + group than in the HC group. Within-group comparisons showed that the C + group had a significantly worse ΔAVLT-DR score (t=-2.167, p = 0.044) compared to the baseline assessment. Conversely, the HC group showed a statistically significant improvement in the ΔAVLT-DR score (t = 2.710, p = 0.014) compared to the baseline assessment (Supplementary Table 3). A comparison of the proportion of CRCI incidence by the difference in changes in PRO showed that the C + group was comparable (42.1%, n = 8) to the HC group (42.1%, n = 8) (Supplementary Fig. 2). Comparing the proportion of individuals with CRCIs using NPTs, the HC group showed a lower proportion of positive rates 31.6% (n = 6), whereas the C + group showed a higher rate of 68.4% (n = 13) after chemotherapy (Supplementary Fig. 3). Comparing the proportions of subscales in between groups, the positive rates of AVLT-DR (31.6%, n = 6) and VFT errors (36.8%, n = 7) were higher in the C + group than in the HC group (Supplementary Fig. 3). As shown by the THb concentration change in Supplementary Fig. 4, a trend of increased task-dependent hemodynamic changes in the lateral prefrontal cortex (LPFC) region compared to the FP region was observed in both groups according to the region of measurement. In terms of time-series changes, a trend towards a decrease in task-dependent hemodynamic changes at six months compared to baseline was observed in both groups. Task-dependent changes in THb concentrations were compared between and within groups, and no statistically significant differences were found in each channel in the between-group comparison (Supplementary Table 4). Within-group comparisons showed a main effect in the left FP region of the C + group (difference in change = -1.6892, CI: -3.0813 to -0.2791, p = 0.018), with a significant reduction in THb concentration change at the six-month follow-up assessment compared to pre-chemotherapy (Fig. 2 ; Supplementary Table 5). Discussion This study investigated changes in CRCI symptoms before and after chemotherapy using subjective PRO and objective NPT assessments, and multidomain assessments using brain function measurements with a portable fNIRS device. There were no significant differences in subjective cognitive complaints between the C + and HC groups. However, objective cognitive performance showed a reduction in delayed recall of verbal memory in the C + group. There was no difference between the groups in prefrontal cortical hemodynamic changes during the VFT task. The comparison within the C + group showed a decrease in the left FP cortical hemodynamics during chemotherapy compared to baseline. The results of PRO using FACT-Cog showed no statistical difference between the two groups in the CogPCI and CogPCA scores, with minimal change within the groups. The proportion of CRCI cases in the C + group was 68.9% with the NPT assessment and 42.1% with the PRO assessment. Discrepancies between the subjective and objective assessments of the CRCI have been reported [ 22 , 23 ], and the present study’s findings agree with those of previous studies. However, previous research on breast cancer survivors reported that cognitive complaints can be more sensitively assessed for CRCI [ 24 ]. The different results in the present study may be related to differences in sex and ethnicity, as patients with gastrointestinal cancer are more likely to be Japanese males. Many older Japanese men consider it undesirable to express their cognitive impairment to others. These sex differences and cultural contexts may suggest that PRO-dependent assessment is not always useful in CRCI studies of all cancers and objective assessment in combination with PRO. Regarding the NPT results, the C + group showed statistically significant reductions in AVLT-DR scores compared to the HC group only in the verbal memory domain, with a significant worsening of AVLT-DR scores in the pre- and post-intervention comparisons within the C + group. There were no statistically significant differences in attentional function, processing speed, or executive function compared with the HC group, whereas some VFT performances were worse in the pre- and post-comparisons within the C + group. A recent systematic review of colorectal cancer survivors showed that colorectal cancer treatment causes negligible changes in NPT performance, and delayed recall of verbal memory functions has a smaller effect size compared to other domains [ 25 ]. The present study showed different results, which may have been influenced by other gastrointestinal cancer diseases and differences in chemotherapy regimens. In addition, a previous study of Asian gastrointestinal cancer survivors showed that decreased attention, processing speed, memory, and executive function during chemotherapy were closely associated with fatigue [ 26 ]. The C + group had a higher rate of co-occurring symptoms, such as fatigue, than the pre-treatment group. However, considering that the cognitive domains impaired in this study were limited to delayed regeneration, with less reduction in attentional function and processing speed, which are closely associated with fatigue, it is suggested that the proportion of fatigue directly affecting cognitive function was small. Additional assessments using objective physiological markers, such as inflammatory markers, rather than subjective fatigue alone, could be a better way to clarify the association between CRCI and fatigue, and this is a limitation of this study. Concerning the measurement of cortical hemodynamic changes using fNIRS, there were no notable differences between the C + and HC groups. A previous study using fNIRS assessment to capture CRCI in breast cancer survivors reported that LPFC hemodynamics and VFT performance were reduced in the chemotherapy treatment group compared to controls [ 11 ]. The difference with the present study is that Duran-Gomez et al. conducted a cross-sectional study that measured only the LPFC. Interestingly, the chemotherapy group in the present study showed decreased activity of the left anterior FP in the within-group comparisons. Generally, neuroimaging studies of VFT tasks have noted increased HbO 2 and THb concentration changes in the LPFC over the FP during the VFT in healthy participants [ 27 ], and the left inferior frontal gyrus is most associated with word production during the VFT [ 28 ]. The FP is a cortical region involved in monitoring internally generated information during multitasking and episodic memory retrieval [ 29 , 30 ]. In the present study, the C + group tended to have a higher left FP activity at baseline. These findings may indicate functional compensation for the temporarily necessary left FPs. Nevertheless, the small sample size requires careful interpretation of the results, and further studies are needed to show the relationship between VFT performance and cerebral hemodynamics in CRCI. Although this was a secondary finding, portable fNIRS has the potential to distinguish confounding factors due to motivational and depressive symptoms in patients with CRCI. In general, neurovascular coupling responses in the prefrontal cortex are significantly reduced in patients with depression [ 31 ]. The study’s findings indicate that the C + group showed at least similar or greater hemodynamic changes in the PFC than the HC group, and physiological parameters indicated that the cognitive decline was not due to depressive symptoms. Monitoring and evaluation of cerebral hemodynamics during cognitive tasks may be useful to validate the motivation to perform tasks and depressive symptoms and compensate for the reliability of those assessments. This study had some limitations. First, its findings have low generalizability owing to selection bias in a single institution. Second, the sample size was small. Third, the follow-up data after chemotherapy were not included. Describing the effects of individual chemotherapy regimens is insufficient; a multidomain evaluation protocol should be used to investigate the effects of each disease and major chemotherapeutic agent in multicenter trials. Conclusion In this prospective cohort study of cognitive changes in gastrointestinal cancer survivors, our findings showed that cancer survivors had lower delayed recall of memory function than healthy controls over six months. Furthermore, analysis of cognitive tasks using P-NIRS showed that cortical hemoglobin concentration changes differed before and after cancer chemotherapy. We believe that the evaluation of cognitive function combined with longitudinal portable NIRS is novel and sufficiently feasible for clinical application in the detection of CRCI. Abbreviations CRCI cancer-related cognitive impairment PRO patient-reported outcomes NVC neurovascular coupling C + cancer chemotherapy HC healthy control VFT verbal fluency test LPFC lateral prefrontal cortex FACT-Cog functional assessment of cancer therapy-cognitive ICCTF international cognition and cancer task force NPT neuropsychological assessment TMT trail making test COWA controlled oral word association test fMRI functional magnetic resonance imaging fNIRS functional near-infrared spectroscopy P-NIRS portable fNIRS ECOG-PS eastern cooperative oncology group-performance status CogPCI perceived cognitive impairments CogPCA perceived cognitive abilities AVLT auditory verbal learning test AVLT-DR AVLT-delayed recall THb total hemoglobin FP frontal pole Declarations Disclosure of potential conflicts of interest The authors have no relevant financial or non-financial interests to disclose Research involving Human Participants This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethical Review Committee for Epidemiological Research of Hiroshima University (25 July 2022 / E2022-0061). Informed consent Informed consent was obtained from all individual participants included in the study. Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethical Review Committee for Epidemiological Research of Hiroshima University (25 July 2022 / E2022-0061). Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: Participants signed informed consent regarding publishing their data and photographs. Funding This work was partly supported by the Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society of the Promotion of Science (Grant number JP23K14734). Author Contribution Conceptualization: Kazuya Saita, Kazuaki Tanabe, Hitoshi Okamura; Data curation: Kazuya Saita, Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Wataru Okamoto, Morihito Okada , Hideki Ohdan; Formal analysis: Kazuya Saita, Kazuaki Tanabe, Fumiko Kaneko, Hitoshi Okamura; Funding acquisition: Kazuya Saita, Hitoshi Okamura; Investigation: Kazuya Saita, Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Fumiko Kaneko, Yukio Mikami, Wataru Okamoto, Morihito Okada, Hideki Ohdan; Methodology: Kazuya Saita, Kazuaki Tanabe, Hitoshi Okamura; Project administration: Hitoshi Okamura; Software: Kazuya Saita, Hitoshi Okamura; Resource: Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Yukio Mikami, Wataru Okamoto, Morihito Okada , Hideki Ohdan; Validation: Kazuya Saita, Fumiko Kaneko; Visualization: Kazuya Saita, Fumiko Kaneko; Writing – original draft: Kazuya Saita, Kazuaki Tanabe, Hitoshi Okamura; Writing – review & editing: Kazuya Saita, Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Fumiko Kaneko, Yukio Mikami, Wataru Okamoto, Morihito Okada , Hideki Ohdan, Hitoshi Okamura Acknowledgments This work was partly supported by the Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society of the Promotion of Science (Grant number JP23K14734). Data Availability Statement: The datasets generated during or analyzed during the current study are available from the corresponding author on reasonable request. References Shapiro CL. Cancer survivorship. N Engl J Med. 2018;379:2438–50. https://doi.org/10.1056/NEJMra1712502 . Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA. ‘Chemobrain’ in breast carcinoma? A prologue: Cancer. 2004;101:466–75. https://doi.org/10.1002/cncr.20393 Simó M, Rifà-Ros X, Rodriguez-Fornells A, Bruna J, Chemobrain. A systematic review of structural and functional neuroimaging studies. Neurosci Biobehav Rev. 2013;37:1311–21. https://doi.org/10.1016/j.neubiorev.2013.04.015 . Lange M, Joly F, Vardy J, Ahles T, Dubois M, Tron L, et al. Cancer-related cognitive impairment: An update on state of the art, detection, and management strategies in cancer survivors. Ann Oncol. 2019;30:1925–40. https://doi.org/10.1093/annonc/mdz410 . 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Front Hum Neurosci. 2023;17:1063674. https://doi.org/10.3389/fnhum.2023.1063674 . Jean-Pierre P. Integrating functional near-infrared spectroscopy in the characterization, assessment, and monitoring of cancer and treatment-related neurocognitive dysfunction. NeuroImage. 2014;85:408–14. https://doi.org/10.1016/j.neuroimage.2013.06.075 . Yao S, Zhang Q, Yao X, Zhang X, Pang L, Yu S, et al. Advances of neuroimaging in chemotherapy related cognitive impairment (CRCI) of patients with breast cancer. Breast Cancer Res Treat. 2023;201:15–26. https://doi.org/10.1007/s10549-023-07005-y . Durán-Gómez N, López-Jurado CF, Nadal-Delgado M, Pérez-Civantos D, Guerrero-Martín J, Cáceres MC. Chemotherapy-related cognitive impairment in patients with breast cancer based on functional assessment and NIRS analysis. J Clin Med. 2022;11. https://doi.org/10.3390/jcm11092363 . Chen BT, Sethi SK, Jin TH, Patel SK, Ye NR, Sun CL, et al. Assessing brain volume changes in older women with breast cancer receiving adjuvant chemotherapy: A brain magnetic resonance imaging pilot study. Breast Cancer Res. 2018;20:38. https://doi.org/10.1186/s13058-018-0965-3 . Bai XR, Zheng J, Zhang B, Luo YH. Cognitive dysfunction and neurophysiologic mechanism of breast cancer patients undergoing chemotherapy based on resting state functional magnetic resonance imaging. World Neurosurg. 2021;149:406–12. https://doi.org/10.1016/j.wneu.2020.10.066 . Komuro Y, Sato Y, Lin L, Tang Z, Hu L, Sakatani K. Reliability of wearable two channel CW-NIRS in measurements of brain function. Adv Exp Med Biol. 2018;1072:301–5. https://doi.org/10.1007/978-3-319-91287-5_48 . Kiguchi M, Funane T. Algorithm for removing scalp signals from functional near-infrared spectroscopy signals in real time using multidistance optodes. J Biomed Opt. 2014;19:110505. https://doi.org/10.1117/1.JBO.19.11.110505 . Tachtsidis I, Scholkmann F. False positives and false negatives in functional near-infrared spectroscopy: Issues, challenges, and the way forward. Neurophotonics. 2016;3:031405. https://doi.org/10.1117/1.NPh.3.3.031405 . Saita K, Ogata T, Watanabe J, Tsuboi Y, Takahara M, Inoue T, et al. Contralateral cerebral hypometabolism after cerebellar stroke: A functional near-infrared spectroscopy study. J Stroke Cerebrovasc Dis. 2017;26:e69–71. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.01.014 . Wada M. Recent memory function on the MMSE and RAVLT in the elderly [in Japanese]. Dement Jpn. 2016;30:280–9. Ishiai SC. Brain function test committee, Japan society for higher brain function 2019. Trail making test. Japanese ed. (TMT-J) [in Japanese]. Shinkoh Igaku Shuppan Co. Ltd . Ito E, Hatta T, Ito Y, Kogure T, Watanabe H. Performance of verbal fluency tasks in Japanese healthy adults: Effect of gender, age and education on the performance [in Japanese]. Jpn J Neuropsychol. 2004;20:254–63. Bell ML, Dhillon HM, Bray VJ, Vardy JL. Important differences and meaningful changes for the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). J Patient Rep Outcomes. 2018;2:ARTN48. https://doi.org/10.1186/s41687-018-0071-4 . Hutchinson AD, Hosking JR, Kichenadasse G, Mattiske JK, Wilson C. Objective and subjective cognitive impairment following chemotherapy for cancer: A systematic review. Cancer Treat Rev. 2012;38:926–34. https://doi.org/10.1016/j.ctrv.2012.05.002 . Boelsbjerg HB, Kurita GP, Sjøgren P, Hansen NV. Combining subjective and objective appraisals of cognitive dysfunction in patients with cancer: A deeper understanding of meaning and impact on suffering? Support Care Cancer. 2022;30:3603–12. https://doi.org/10.1007/s00520-021-06777-7 . Janelsins MC, Heckler CE, Peppone LJ, Kamen C, Mustian KM, Mohile SG, et al. Cognitive complaints in survivors of breast cancer after chemotherapy compared with age-matched controls: An analysis from a nationwide, multicenter, prospective longitudinal study. J Clin Oncol. 2017;35:506–14. https://doi.org/10.1200/JCO.2016.68.5826 . Hwang SY, Kim K, Ha B, Lee D, Kim S, Ryu S, et al. Neurocognitive effects of chemotherapy for colorectal cancer: A systematic review and a meta-analysis of 11 studies. Cancer Res Treat. 2021;53:1134–47. https://doi.org/10.4143/crt.2020.1191 . Oh PJ, Moon SM. Changes of Cognitive Function and Fatigue following Chemotherapy in Patients with gastrointestinal Cancer: A Prospective Controlled Study. Asian Oncol Nurs. 2019;19:126–34. https://doi.org/10.5388/aon.2019.19.3.126 . Takizawa R, Kasai K, Kawakubo Y, Marumo K, Kawasaki S, Yamasue H, et al. Reduced frontopolar activation during verbal fluency task in schizophrenia: A multi-channel near-infrared spectroscopy study. Schizophr Res. 2008;99:250–62. https://doi.org/10.1016/j.schres.2007.10.025 . Costafreda SG, Fu CHY, Lee L, Everitt B, Brammer MJ, David AS. A systematic review and quantitative appraisal of fMRI studies of verbal fluency: Role of the left inferior frontal gyrus. Hum Brain Mapp. 2006;27:799–810. https://doi.org/10.1002/hbm.20221 . Düzel E, Cabeza R, Picton TW, Yonelinas AP, Scheich H, Heinze HJ, et al. Task-related and item-related brain processes of memory retrieval. Proc Natl Acad Sci U S A. 1999;96:1794–9. DOI.https://doi.org/10.1073/pnas.96.4.1794 . Christoff K, Gabrieli JDE. The frontopolar cortex and human cognition: Evidence for a rostrocaudal hierarchical organization within the human prefrontal cortex. Psychobiology. 2000;28:168–86. https://doi.org/10.3758/BF03331976 . Yeung MK, Lin JX. Probing depression, schizophrenia, and other psychiatric disorders using fNIRS and the verbal fluency test: A systematic review and meta-analysis. J Psychiatr Res. 2021;140:416–35. https://doi.org/10.1016/j.jpsychires.2021.06.015 . Statements & Declarations Additional Declarations No competing interests reported. Supplementary Files Supplementaryfile1.pdf Cite Share Download PDF Status: Published Journal Publication published 15 Feb, 2025 Read the published version in Journal of Cancer Survivorship → Version 1 posted Editorial decision: Revision requested 17 Oct, 2024 Reviews received at journal 10 Oct, 2024 Reviewers agreed at journal 06 Oct, 2024 Reviewers agreed at journal 05 Oct, 2024 Reviewers invited by journal 04 Oct, 2024 Editor assigned by journal 04 Oct, 2024 Submission checks completed at journal 04 Oct, 2024 First submitted to journal 02 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5191114","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":367095444,"identity":"276d0fa8-98e9-45bb-980f-039d56404eb8","order_by":0,"name":"Kazuya Saita","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIie3QsYrCMBjA8U8KdYnOEQq+QkHQzXuVBgcXN5cDBRsEsyh9gDvuGXTJHAjokgdwcGiXTDfoIjoc+NXByRa7HZI/BELgx5cEwOX6l9VigE9FcOdD9DglpYTHYKoRHFNbKLiTl2oLLdLrzyHoCWHTbNSHUHnZEYJDIQkN43wlLQmM6YVMDpD4HQrEFhNgPG5ITSgd+ZRJb7ZW0MW36OKLJRnnf985GVokM5xSP5cS2DM+b8Q5ibpINBJSPiXcZ/wr2CIhJic7aGkyplHJW9rJMD39TvUHrQvbusoJNHdiczwti3/sSR4utlRVyL1LdeJyuVxv2w1CtlaxEFWLyAAAAABJRU5ErkJggg==","orcid":"","institution":"Hiroshima University","correspondingAuthor":true,"prefix":"","firstName":"Kazuya","middleName":"","lastName":"Saita","suffix":""},{"id":367095446,"identity":"d9e4e26d-ab5c-468d-9de7-e1f39e368a37","order_by":1,"name":"Kazuaki Tanabe","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Kazuaki","middleName":"","lastName":"Tanabe","suffix":""},{"id":367095448,"identity":"1bc6579e-e397-416f-9772-4263896485d2","order_by":2,"name":"Yoichi Hamai","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Yoichi","middleName":"","lastName":"Hamai","suffix":""},{"id":367095451,"identity":"bdd261e3-885f-4c0f-bf2f-d2895e7c107e","order_by":3,"name":"Masami Yamauchi","email":"","orcid":"","institution":"Hiroshima Prefectural Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masami","middleName":"","lastName":"Yamauchi","suffix":""},{"id":367095452,"identity":"6222d86a-dff9-4559-b3b6-94a0dce8d594","order_by":4,"name":"Fumiko Kaneko","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Fumiko","middleName":"","lastName":"Kaneko","suffix":""},{"id":367095454,"identity":"4a388fb0-db5b-41d7-94f0-5919274e368b","order_by":5,"name":"Yukio Mikami","email":"","orcid":"","institution":"Hiroshima University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yukio","middleName":"","lastName":"Mikami","suffix":""},{"id":367095457,"identity":"3ddc0190-a730-417d-900a-541e1faef41b","order_by":6,"name":"Wataru Okamoto","email":"","orcid":"","institution":"Hiroshima University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wataru","middleName":"","lastName":"Okamoto","suffix":""},{"id":367095458,"identity":"685599cc-f4a0-457a-a14c-1c5ada399772","order_by":7,"name":"Morihito Okada","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Morihito","middleName":"","lastName":"Okada","suffix":""},{"id":367095459,"identity":"9605f3d8-10f9-4531-a646-14305625aabc","order_by":8,"name":"Hideki Ohdan","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Ohdan","suffix":""},{"id":367095461,"identity":"d5a140a4-70a7-4713-8206-7fe198163486","order_by":9,"name":"Hitoshi Okamura","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Okamura","suffix":""}],"badges":[],"createdAt":"2024-10-02 06:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5191114/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5191114/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11764-025-01759-8","type":"published","date":"2025-02-15T15:57:48+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":68538672,"identity":"f8565352-51d1-47d1-9138-63cbbb586673","added_by":"auto","created_at":"2024-11-08 10:30:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":522733,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparisons of cognitive functional assessment between groups. A) Patient-reported outcomes using FACT-Cog. B) Neuropsychological tests.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eError bars indicate standard error. The scores for all the assessment tools were positive for higher cognitive performance.\u003c/p\u003e","description":"","filename":"Figure1JCansurvivorship.png","url":"https://assets-eu.researchsquare.com/files/rs-5191114/v1/77aab0d125cb453916bc1797.png"},{"id":68538671,"identity":"14fcd65a-1ebc-4f90-84b9-41af70159eae","added_by":"auto","created_at":"2024-11-08 10:30:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":512823,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWithin-group comparison of changes in total Hb concentration in the prefrontal cortex\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2JCansurvivorship.png","url":"https://assets-eu.researchsquare.com/files/rs-5191114/v1/2607514230f25368ff68cb33.png"},{"id":76488414,"identity":"906d3e4d-5cb6-4330-9c20-6e95710b9359","added_by":"auto","created_at":"2025-02-17 16:14:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1903565,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5191114/v1/b09abac6-4030-492f-8293-7c806fdc5d83.pdf"},{"id":68538673,"identity":"36ac78bb-32ae-4c04-b924-e7bcc21fdd2b","added_by":"auto","created_at":"2024-11-08 10:30:08","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":2802203,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5191114/v1/11fafb393574d017d4e07ca5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Changes in chemotherapy-induced cognitive impairment in gastrointestinal cancer survivors using multidomain assessments: a prospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe number of cancer cases continues to increase worldwide, and the number of cancer survivors has increased owing to advances in technology and early detection of cancer. One problem with cancer survivorship care is cancer-related cognitive impairment (CRCI) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Chemotherapy-induced cognitive dysfunction is a major impairment experienced by cancer survivors during the treatment process and is also known as \u0026ldquo;\u003cem\u003eChemobrain\u003c/em\u003e\u0026rdquo; [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The degree of impairment in CRCI is similar to that in mild cognitive disorders. Specific cognitive domains include attention, processing speed, memory, and executive function. Several factors are thought to be associated with the occurrence of CRCI, including the cancer itself, effects of cancer treatment (e.g., chemotherapy, hormone therapy), co-occurring symptoms (e.g., fatigue, distress), genetic factors (e.g., APOE-4), physiological factors (e.g., dysregulation of inflammatory cytokines, disruption of the blood-brain barrier), and sociodemographic factors (age, education level) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These factors complicate our understanding of CRCI symptoms.\u003c/p\u003e \u003cp\u003eThe recommendations of the International Cognition and Cancer Task Force (ICCTF) include several statements for study designs to capture CRCI: 1) longitudinal studies that include pre- and post-treatment, 2) disease-specific and healthy control groups, and 3) neuroimaging data for objective and subjective assessment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Regarding assessment methods for CRCI, the ICCTF has recommended the following neuropsychological assessments (NPTs): the Trail Making Test (TMT), Hopkins Verbal Learning Test-Revised, and Controlled Oral Word Association Test (COWA) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Nevertheless, 10 years after their advocacy, these recommended assessments are not being used worldwide for CRCI assessment, and a consensus is yet to be established [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This may be because although NPTs are relatively widespread worldwide, the assessments are language-mediated and have not been standardized in minority language-speaking countries. As similar verbal memory and word fluency tests exist in all countries, reports from minority-language countries are necessary to understand the incidence of CRCI. On the other hand, patient-reported outcomes (PROs) as subjective assessments are also sensitive for CRCI detection. The Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) version 3 is the most frequently used international assessment of PRO assessing CRCI [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to these cognitive assessments, neurophysiological biomarkers measuring brain activity are recommended as adjunct diagnostic tools. Several neuroimaging devices are used to measure brain activity, and functional magnetic resonance imaging (fMRI) is a representative device. However, given its clinical application, applying fMRI to all non-central nervous system cancers is not feasible from an economic and time-effective perspective. Functional near-infrared spectroscopy (fNIRS) is a noninvasive neuroimaging method that addresses this problem. fNIRS measures changes in cerebral blood flow associated with neural activity based on the neurovascular coupling (NVC) response. The fNIRS device is expected to bridge the gap between NPT and PRO as an adjunct diagnostic tool for current cognitive function assessment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In this study, we applied portable fNIRS (P-NIRS), which is less restraining and burdensome to patients and can be used under conditions similar to those in daily life. To our knowledge, only one study has reported the clinical application of fNIRS measurements in addition to NPT and PRO to detect CRCI in breast cancer [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and none has reported on the use of the P-NIRS device in gastrointestinal cancer.\u003c/p\u003e \u003cp\u003eThis study aimed to prospectively investigate neurocognitive changes in gastrointestinal cancer survivors before and after chemotherapy using a multidomain assessment and compare them with healthy volunteers. To capture neurocognitive changes from multiple perspectives, the secondary aim was to investigate the feasibility of clinical applications for measuring cortical hemodynamic changes based on NVC responses as an additional diagnostic tool in conjunction with cognitive functional assessments.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThis study prospectively recruited 48 volunteers to enroll between September 2022 and December 2023, 24 each in the cancer chemotherapy (C+) and healthy control (HC) groups. Each participant was enrolled after eligibility checks with written consent after providing informed consent for the study. Measurements were completed before chemotherapy or baseline assessments and then after six-month follow-up assessments and were evaluated under the same environmental conditions. Based on previous neuroimaging studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], we estimated the feasible number of participants from previous outpatients at our single institution and decided on a sample size of 40: 20 in the C\u0026thinsp;+\u0026thinsp;group and 20 in the age- and sex-matched HC group. Assuming a dropout rate of 10%, a total of 48 cases were included in this study. This study was approved by the Ethical Review Committee for Epidemiological Research of Hiroshima University (E2022-0061).\u003c/p\u003e \u003cp\u003eThe C\u0026thinsp;+\u0026thinsp;group included outpatients at the Hiroshima University Hospital who were to begin their first course of chemotherapy following a diagnosis of gastrointestinal cancer (colorectal, gastric, or esophageal cancer). The HC group recruited healthy volunteers without cancer or central diseases from staff or family members of patients in outpatient rehabilitation facilities and community centers in the same residential area. The inclusion criteria for the C\u0026thinsp;+\u0026thinsp;group were as follows: 1) individuals who were at least 20 years and \u0026lt;\u0026thinsp;85 years old, 2) individuals who met the diagnostic criteria for gastrointestinal cancer (colorectal cancer, gastric cancer, esophageal cancer), 3) individuals who were scheduled to start the first course of chemotherapy treatment, 4) individuals with no anemic symptoms and a hemoglobin level of \u0026gt;\u0026thinsp;8.0 g/dl on a blood test, 5) individuals with an Eastern Cooperative Oncology Group- performance status score (ECOG-PS) of 0 or 1, 6) individuals whose first language is Japanese, 7) individuals scheduled for outpatient visits for at least six-months, and 8) individuals who provided written consent to participate in this study. The exclusion criteria were as follows: 1) individuals with a history of chemotherapy treatment for cancer, 2) individuals with a diagnosis of dementia or cognitive decline equivalent to dementia (Mini-Mental State Examination, Japanese version, less than 24 points), 3) individuals with a diagnosis of severe depression or psychiatric disorder, 4) individuals regularly using sleeping pills due to sleep disorders, 5) individuals with primary brain tumors, metastases or disorders to the central nervous system, 6) individuals with a history of alcohol or drug addiction, 7) individuals with a history of opioid analgesic use due to cancer pain, 8) individuals with cachexia or other poor systemic conditions, 9) individuals with serious liver disease, renal disease, seizure disorder, cardiac complications, 10) pregnant and lactating women, and 11) other individuals judged to be inappropriate by the principal investigator. It was planned to exclude from the analysis cases where follow-up data could not be obtained due to an individual's unanticipated life events or individual intent. Individuals for whom follow-up data were not available due to an unforeseen life events were planned to be excluded from the analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAssessments and fNIRS measurements\u003c/h3\u003e\n\u003cp\u003eDuring the eligibility check, the following information was collected from the individuals as sociodemographic factors related to cognitive function: age, sex, education level, marital status, and employment status. Clinical characteristics, including tumor stage, cancer site, line of therapy, and chemotherapy regimens, were collected from the electronic medical records at our facility. In both groups, the Mini-Mental State Examination, Japanese version, and the Japanese Adult Reading Test were used to assess cognitive functional screening and predict IQ as a cognitive reserve at baseline. In the C\u0026thinsp;+\u0026thinsp;group, the co-occurring symptoms of cancer-related fatigue, sleep disturbances, and pain were investigated through self-reporting; anemia was screened based on blood hemoglobin levels.\u003c/p\u003e \u003cp\u003eFACT-Cog version 3 was used to assess subjective cognitive complaints. The FACT-Cog is a 37-item, 5-point questionnaire that assesses perceived cognitive decline and recommends the use of sub-items rather than the total score, as it is divided into four sub-items. The study used scores for perceived cognitive impairments (CogPCI: score range 0\u0026ndash;72) and perceived cognitive abilities (CogPCA: score range, 0\u0026ndash;28).\u003c/p\u003e \u003cp\u003eThe Japanese versions of the TMT (TMT-J), Rey auditory verbal learning test (AVLT), and verbal fluency test (VFT) were used to evaluate objective cognitive function. The performance time of the TMT-J was assessed for part A (a task to connect numbers in sequence) to measure the processing speed domain and part B (a task to connect numbers and letters alternately) to measure the executive function domain. The AVLT was used to assess the verbal memory domain, and the following main outcome measures were assessed: total number of words from the first to fifth (AVLT-sum) and number of delayed recalls (AVLT-DR/AVLT-7). A letter fluency task was selected for the VFT to assess the language and executive function domains. The total number of 3 mora generated per 60 s was recorded according to COWA, and the number of generated words and duplicate errors for each mora (/a/ /ka/ /shi/) were recorded.\u003c/p\u003e \u003cp\u003eContinuous-wave P-NIRS (HOT-2000, NeU Corporation, Tokyo, Japan) is a wireless device with a Bluetooth connection. The sampling rate was 10 Hz, and the wavelength of the near-infrared light was 810 nm. This device allows the measurement of changes in total hemoglobin (THb) concentration according to the modified Beer\u0026ndash;Lambert law; the reliability of prefrontal cortex measurements compared to multichannel fNIRS has been demonstrated by prior P-NIRS devices [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The NVC response is the principle of fNIRS measurements, and THb is one of the representative indicators of fNIRS, which represents the sum of oxyhemoglobin (O\u003csub\u003e2\u003c/sub\u003eHb) and deoxyhemoglobin (HHb) concentrations. In a typical NVC reaction, THb and O\u003csub\u003e2\u003c/sub\u003eHb concentrations increase if HHb remains unchanged. The P-NIRS instrument incorporates a multi-distance optodesis method [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] that removes the skin blood flow component by implementing a short channel to compensate for the shortcomings of previous NIRS studies [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Based on the International 10\u0026ndash;20 method, the positions of the left and right channels were defined as the positions corresponding to the frontal pole (FP) on the Fp1 and Fp2 lines or the lateral region (corresponding to part of the ventral and dorsal prefrontal cortex) as the lateral prefrontal cortex (LPFC). The participants in the P-NIRS experiment were seated in a quiet environment. The experiment used a block design method, and the most commonly used letter fluency task was the cognitive task for the fNIRS experiment. Based on previous studies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], a modified protocol was used, in which, after an initial 30-s rest period, a 120-s cycle consisting of a 30-s control task, a 60-s phonemic fluency task, and a 30-s recovery task was repeated three times. The control task consisted of repeated vocalizations of the Japanese vowels (/a/, /i/, /u/, /e/, and /o/). The VFT comprised two sets of three 60-s repetitions of one mora as a phonemic fluency task (/shi/, /i/, /re/, or /a/, /fu/, /ni/).\u003c/p\u003e\n\u003ch3\u003eAnalysis\u003c/h3\u003e\n\u003cp\u003eRepresentative values for sociodemographic data, clinical characteristics, and cognitive functional assessment are expressed as means or medians, depending on the skewness of the distribution of the descriptive data. The Shapiro\u0026ndash;Wilk test was used to test for normality. To compare the baseline characteristics and clinical data between the groups, we used the two-sample t-test or Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables. Several parameters of the objective cognitive assessment using NPTs were transformed into age-matched normalized scores (Z-score) based on previous studies to obtain consistent descriptive data [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The TMT-A, TMT-B, and VFT-error were flipped values of the Z-score used so that the positive direction of cognitive performance had a better score. Welch\u0026rsquo;s two-sample t-test was used to compare differences in changes between the groups in each cognitive function assessment. Missing data without follow-up assessments were excluded. To compare within-group data, the paired t-test or Wilcoxon signed-rank test was used. To calculate the percentage of CRCI incidence, PRO and NPT were based on the following methods: for NPT, the ICCTF-recommended criteria for CRCI were used, defined as \u0026ge;\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 SD of the standard for two NPTs or \u0026ge;\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 SD for one NPT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]; for PRO by FACT-Cog, the clinically important difference in FACT-Cog was defined as subscale scores ranging from 6.4 to 10.3%, so we defined this as a decrease of at least 4.6 points (6.4% decrease) on the CogPCI score or at least 1.8 points (6.4% decrease) on the CogPCA [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor the fNIRS analysis, pre-processing of the raw data was performed using the statistical analysis software TOMATO (HOT-ANALYSIS; NeU Corporation, Tokyo, Japan). A median filter and moving average were used for noise reduction. First, the median filter was set to a time window of 1 s to reduce the spike noise caused by body movement. Subsequently, the moving average was set to 3 s to smoothen the waveform data. The smoothed waveform data were averaged, and a baseline correction was performed with the task start time set to zero. To allow for inter-channel and inter-subject comparisons, we converted the Z-score to represent the change in THb concentration. It was converted to a normalized averaging waveform by dividing by the standard deviation of the 20 s value of the control task. Matlab R 2023a (Mathworks, Inc., Natick, MA, USA) was used to analyze the fNIRS data after pre-processing. Linear mixed models were used for between-group and within-group comparisons of the fNIRS data. The fixed effects were group (C\u0026thinsp;+\u0026thinsp;and HC groups), period (baseline and follow-up), and task condition (control task and VFT task), whereas the random effects were individual participants. The two-sided significance level was set at 5%. All statistical analyses were performed using JMP pro 17.0.0 (SAS Institute Inc., Cary, NC, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAfter eligibility checks, 48 participants (24 volunteers each in the C\u0026thinsp;+\u0026thinsp;and HC groups) were enrolled, and 38 participants (19 in each group; median age, 74 years; 12 men and 7 women, respectively) were finally included in this study. Of the five individuals in the C\u0026thinsp;+\u0026thinsp;group who dropped out, four died, and one was difficult to follow up due to outpatient treatment outside the prefecture. Of the five individuals in the HC group who dropped out, two had surgery due to orthopedical conditions, and two were hospitalized due to cardiac and cerebrovascular diseases and, therefore, could not undergo follow-up assessments. The other did not wish to be followed up due to the bereavement of a family member. Baseline socio-demographics and clinical characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003eand\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBetween-group comparisons of socio-demographic characteristics and cognitive assessments at baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (N\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003cp\u003emean [95%CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC\u0026thinsp;+\u0026thinsp;group (N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e \u003cp\u003emean [95%CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHC group (N\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e \u003cp\u003emean [95%CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eSocio-demographic characteristics\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (64-79.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (67\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (49\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.977\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003cp\u003emen (%)\u003c/p\u003e \u003cp\u003ewomen (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (63.2)\u003c/p\u003e \u003cp\u003e14 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (63.2)\u003c/p\u003e \u003cp\u003e7 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (63.2)\u003c/p\u003e \u003cp\u003e7 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRace/Ethnicity\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAsian/Japanese (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEducation level\u003c/b\u003e\u003c/p\u003e \u003cp\u003ehigh school (12 ≧) (%)\u003c/p\u003e \u003cp\u003ecollege (12 \u0026lt;) (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (60.5)\u003c/p\u003e \u003cp\u003e15 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (68.4)\u003c/p\u003e \u003cp\u003e6 (31.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (52.6)\u003c/p\u003e \u003cp\u003e9 (47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.319\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMarital status\u003c/b\u003e\u003c/p\u003e \u003cp\u003esingle (%)\u003c/p\u003e \u003cp\u003emarried (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (13.2)\u003c/p\u003e \u003cp\u003e33 (86.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (15.8)\u003c/p\u003e \u003cp\u003e16 (84.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (10.5)\u003c/p\u003e \u003cp\u003e17 (89.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.631\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEmployment status\u003c/b\u003e\u003c/p\u003e \u003cp\u003eunemployed (%)\u003c/p\u003e \u003cp\u003ebeing employed (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (57.9)\u003c/p\u003e \u003cp\u003e16 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (73.7)\u003c/p\u003e \u003cp\u003e5 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (42.1)\u003c/p\u003e \u003cp\u003e11 (57.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.049\u003csup\u003ec*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eObjective cognitive assessments\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMMSE\u003c/b\u003e, score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (28\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (29\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (28\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.772\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eJART\u003c/b\u003e, FSIQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102.58 [99.11, 105.89]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100.21 [94.98, 105.45]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e104.79 [100.23, 109.35]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.175\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTMT-A\u003c/b\u003e, sec, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (33-63.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (33\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51 (34\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.759\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTMT-B\u003c/b\u003e, sec, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.5 (60.5\u0026ndash;103)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (59\u0026ndash;119)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75 (67\u0026ndash;98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.781\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVLT-sum\u003c/b\u003e, words\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.92 [35.55\u0026ndash;42.29]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.11 [32.07, 42.14]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40.74 [35.93, 45.55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.281\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVLT-DR\u003c/b\u003e, words\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.58 [6.51, 8.65]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.32 [5.65, 8.99]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.84 [6.36, 9.33]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.624\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVFT-sum\u003c/b\u003e, words\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.84 [29.09, 36.60]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.89 [27.83, 37.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.79 [26.74, 38.84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.978\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVFT-error\u003c/b\u003e, words\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.97 [1.27, 2.68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.42 [1.59, 2.42]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.52 [0.34, 2.71]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.202\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSubjective cognitive assessments, FACT-Cog\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCog PCI\u003c/b\u003e, score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.5 (60.5\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (59\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (61\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.568\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCog PCA\u003c/b\u003e, score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (22\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (22\u0026ndash;26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (22\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.385\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAVLT-DR, (Rey) Auditory Verbal Learning Test - delayed recall (Trial 7); AVLT-sum, (Rey) Auditory Verbal Learning Test - sum (Trial 1\u0026ndash;5); C\u0026thinsp;+\u0026thinsp;group, Cancer chemotherapy group; CI, confidence interval; Cog-PCA, cognitive function \u0026ndash; perceived cognitive ability; Cog-PCI, cognitive function \u0026ndash; perceived cognitive impairment; FACT-Cog, Functional Assessment of Cancer Therapy - Cognitive Function; FSIQ, Full-scale intelligence quotient; HC group, healthy control group; IQR, Interquartile range; JART, Japanese Adult Reading Test; MMSE, Mini-Mental State Examination; TMT-A, Trail Making Test- part A; TMT-B, Trail Making Test - part B; VFT-sum, Verbal (Phenomic) Fluency Test - total cumulative number for three mora, VFT-error, Verbal (Phenomic) Fluency Test - number of repeated errors for the three mora\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003ea, two sample t-test; b, Wilcoxon rank sum test; c, square-test; *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics in the cancer chemothrapy group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eⅠ\u003c/p\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003cp\u003eⅢ\u003c/p\u003e \u003cp\u003eⅣ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCancer sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eColorectum\u003c/p\u003e \u003cp\u003eStomach\u003c/p\u003e \u003cp\u003eOesophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLine of therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e \u003cp\u003eNeoadjuvant chemotherapy\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003cp\u003eChemoradiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChemotherapy regimen\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDCF\u003c/p\u003e \u003cp\u003eCAPOX\u003c/p\u003e \u003cp\u003eSOX\u0026thinsp;+\u0026thinsp;HER\u003c/p\u003e \u003cp\u003eSOX\u0026thinsp;+\u0026thinsp;NIVO\u003c/p\u003e \u003cp\u003eNIVO\u0026thinsp;+\u0026thinsp;IPI\u003c/p\u003e \u003cp\u003eS-1\u003c/p\u003e \u003cp\u003eCF\u003c/p\u003e \u003cp\u003eCF\u0026thinsp;+\u0026thinsp;NIVO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemoglobin level\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eg/dl (SD) [95%CI]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.31 (1.80)\u003c/p\u003e \u003cp\u003e[11.44\u0026ndash;13.18]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.74 (1.53)\u003c/p\u003e \u003cp\u003e[10.97\u0026ndash;12.50]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCo-occurring symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFatigue (%)\u003c/p\u003e \u003cp\u003eSleep disturbance (%)\u003c/p\u003e \u003cp\u003ePain (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.2)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (36.8)\u003c/p\u003e \u003cp\u003e4 (21.1)\u003c/p\u003e \u003cp\u003e1 (5.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCAPOX, capecitabine\u0026thinsp;+\u0026thinsp;oxaliplatin; CF, cisplatin\u0026thinsp;+\u0026thinsp;5-FU; CI, confidence interval; DCF, docetaxel\u0026thinsp;+\u0026thinsp;cisplatin\u0026thinsp;+\u0026thinsp;5-FU; HER, trastuzumab; IPI, Ipilimumab; NIVO, nivolumab; SD, standard deviation; SOX, S-1\u0026thinsp;+\u0026thinsp;oxaliplatin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eComparisons between the C\u0026thinsp;+\u0026thinsp;and HC groups at the baseline cognitive functional assessment showed no statistically significant difference in PRO and NPT scores (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e ; Supplementary Table\u0026nbsp;1). The change in PRO and NPT between groups was not significantly different in the ΔCogPCI or ΔCogPCA scores on the FACT-Cog (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). A comparison of the NPT between the groups showed a statistically significant difference (t\u0026thinsp;=\u0026thinsp;3.365, p\u0026thinsp;=\u0026thinsp;0.002, d\u0026thinsp;=\u0026thinsp;1.092) in the ΔAVLT-DR but no statistically significant change in the other NPT scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB; Supplementary Table\u0026nbsp;2). As shown in Supplementary Fig.\u0026nbsp;1, the NPT scores showed an overall trend toward lower cognitive performance in the C\u0026thinsp;+\u0026thinsp;group than in the HC group. Within-group comparisons showed that the C\u0026thinsp;+\u0026thinsp;group had a significantly worse ΔAVLT-DR score (t=-2.167, p\u0026thinsp;=\u0026thinsp;0.044) compared to the baseline assessment. Conversely, the HC group showed a statistically significant improvement in the ΔAVLT-DR score (t\u0026thinsp;=\u0026thinsp;2.710, p\u0026thinsp;=\u0026thinsp;0.014) compared to the baseline assessment (Supplementary Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA comparison of the proportion of CRCI incidence by the difference in changes in PRO showed that the C\u0026thinsp;+\u0026thinsp;group was comparable (42.1%, n\u0026thinsp;=\u0026thinsp;8) to the HC group (42.1%, n\u0026thinsp;=\u0026thinsp;8) (Supplementary Fig.\u0026nbsp;2). Comparing the proportion of individuals with CRCIs using NPTs, the HC group showed a lower proportion of positive rates 31.6% (n\u0026thinsp;=\u0026thinsp;6), whereas the C\u0026thinsp;+\u0026thinsp;group showed a higher rate of 68.4% (n\u0026thinsp;=\u0026thinsp;13) after chemotherapy (Supplementary Fig.\u0026nbsp;3). Comparing the proportions of subscales in between groups, the positive rates of AVLT-DR (31.6%, n\u0026thinsp;=\u0026thinsp;6) and VFT errors (36.8%, n\u0026thinsp;=\u0026thinsp;7) were higher in the C\u0026thinsp;+\u0026thinsp;group than in the HC group (Supplementary Fig.\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eAs shown by the THb concentration change in Supplementary Fig.\u0026nbsp;4, a trend of increased task-dependent hemodynamic changes in the lateral prefrontal cortex (LPFC) region compared to the FP region was observed in both groups according to the region of measurement. In terms of time-series changes, a trend towards a decrease in task-dependent hemodynamic changes at six months compared to baseline was observed in both groups. Task-dependent changes in THb concentrations were compared between and within groups, and no statistically significant differences were found in each channel in the between-group comparison (Supplementary Table\u0026nbsp;4). Within-group comparisons showed a main effect in the left FP region of the C\u0026thinsp;+\u0026thinsp;group (difference in change = -1.6892, CI: -3.0813 to -0.2791, p\u0026thinsp;=\u0026thinsp;0.018), with a significant reduction in THb concentration change at the six-month follow-up assessment compared to pre-chemotherapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Supplementary Table\u0026nbsp;5).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated changes in CRCI symptoms before and after chemotherapy using subjective PRO and objective NPT assessments, and multidomain assessments using brain function measurements with a portable fNIRS device. There were no significant differences in subjective cognitive complaints between the C\u0026thinsp;+\u0026thinsp;and HC groups. However, objective cognitive performance showed a reduction in delayed recall of verbal memory in the C\u0026thinsp;+\u0026thinsp;group. There was no difference between the groups in prefrontal cortical hemodynamic changes during the VFT task. The comparison within the C\u0026thinsp;+\u0026thinsp;group showed a decrease in the left FP cortical hemodynamics during chemotherapy compared to baseline.\u003c/p\u003e \u003cp\u003eThe results of PRO using FACT-Cog showed no statistical difference between the two groups in the CogPCI and CogPCA scores, with minimal change within the groups. The proportion of CRCI cases in the C\u0026thinsp;+\u0026thinsp;group was 68.9% with the NPT assessment and 42.1% with the PRO assessment. Discrepancies between the subjective and objective assessments of the CRCI have been reported [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and the present study\u0026rsquo;s findings agree with those of previous studies. However, previous research on breast cancer survivors reported that cognitive complaints can be more sensitively assessed for CRCI [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The different results in the present study may be related to differences in sex and ethnicity, as patients with gastrointestinal cancer are more likely to be Japanese males. Many older Japanese men consider it undesirable to express their cognitive impairment to others. These sex differences and cultural contexts may suggest that PRO-dependent assessment is not always useful in CRCI studies of all cancers and objective assessment in combination with PRO.\u003c/p\u003e \u003cp\u003e Regarding the NPT results, the C\u0026thinsp;+\u0026thinsp;group showed statistically significant reductions in AVLT-DR scores compared to the HC group only in the verbal memory domain, with a significant worsening of AVLT-DR scores in the pre- and post-intervention comparisons within the C\u0026thinsp;+\u0026thinsp;group. There were no statistically significant differences in attentional function, processing speed, or executive function compared with the HC group, whereas some VFT performances were worse in the pre- and post-comparisons within the C\u0026thinsp;+\u0026thinsp;group. A recent systematic review of colorectal cancer survivors showed that colorectal cancer treatment causes negligible changes in NPT performance, and delayed recall of verbal memory functions has a smaller effect size compared to other domains [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The present study showed different results, which may have been influenced by other gastrointestinal cancer diseases and differences in chemotherapy regimens. In addition, a previous study of Asian gastrointestinal cancer survivors showed that decreased attention, processing speed, memory, and executive function during chemotherapy were closely associated with fatigue [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The C\u0026thinsp;+\u0026thinsp;group had a higher rate of co-occurring symptoms, such as fatigue, than the pre-treatment group. However, considering that the cognitive domains impaired in this study were limited to delayed regeneration, with less reduction in attentional function and processing speed, which are closely associated with fatigue, it is suggested that the proportion of fatigue directly affecting cognitive function was small. Additional assessments using objective physiological markers, such as inflammatory markers, rather than subjective fatigue alone, could be a better way to clarify the association between CRCI and fatigue, and this is a limitation of this study.\u003c/p\u003e \u003cp\u003eConcerning the measurement of cortical hemodynamic changes using fNIRS, there were no notable differences between the C\u0026thinsp;+\u0026thinsp;and HC groups. A previous study using fNIRS assessment to capture CRCI in breast cancer survivors reported that LPFC hemodynamics and VFT performance were reduced in the chemotherapy treatment group compared to controls [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The difference with the present study is that Duran-Gomez et al. conducted a cross-sectional study that measured only the LPFC. Interestingly, the chemotherapy group in the present study showed decreased activity of the left anterior FP in the within-group comparisons. Generally, neuroimaging studies of VFT tasks have noted increased HbO\u003csub\u003e2\u003c/sub\u003e and THb concentration changes in the LPFC over the FP during the VFT in healthy participants [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and the left inferior frontal gyrus is most associated with word production during the VFT [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The FP is a cortical region involved in monitoring internally generated information during multitasking and episodic memory retrieval [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In the present study, the C\u0026thinsp;+\u0026thinsp;group tended to have a higher left FP activity at baseline. These findings may indicate functional compensation for the temporarily necessary left FPs. Nevertheless, the small sample size requires careful interpretation of the results, and further studies are needed to show the relationship between VFT performance and cerebral hemodynamics in CRCI. Although this was a secondary finding, portable fNIRS has the potential to distinguish confounding factors due to motivational and depressive symptoms in patients with CRCI. In general, neurovascular coupling responses in the prefrontal cortex are significantly reduced in patients with depression [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The study\u0026rsquo;s findings indicate that the C\u0026thinsp;+\u0026thinsp;group showed at least similar or greater hemodynamic changes in the PFC than the HC group, and physiological parameters indicated that the cognitive decline was not due to depressive symptoms. Monitoring and evaluation of cerebral hemodynamics during cognitive tasks may be useful to validate the motivation to perform tasks and depressive symptoms and compensate for the reliability of those assessments.\u003c/p\u003e \u003cp\u003eThis study had some limitations. First, its findings have low generalizability owing to selection bias in a single institution. Second, the sample size was small. Third, the follow-up data after chemotherapy were not included. Describing the effects of individual chemotherapy regimens is insufficient; a multidomain evaluation protocol should be used to investigate the effects of each disease and major chemotherapeutic agent in multicenter trials.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this prospective cohort study of cognitive changes in gastrointestinal cancer survivors, our findings showed that cancer survivors had lower delayed recall of memory function than healthy controls over six months. Furthermore, analysis of cognitive tasks using P-NIRS showed that cortical hemoglobin concentration changes differed before and after cancer chemotherapy. We believe that the evaluation of cognitive function combined with longitudinal portable NIRS is novel and sufficiently feasible for clinical application in the detection of CRCI.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecancer-related cognitive impairment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epatient-reported outcomes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNVC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneurovascular coupling\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eC\u0026thinsp;+\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecancer chemotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehealthy control\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVFT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003everbal fluency test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLPFC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elateral prefrontal cortex\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFACT-Cog\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efunctional assessment of cancer therapy-cognitive\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICCTF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einternational cognition and cancer task force\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNPT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneuropsychological assessment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTMT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etrail making test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOWA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econtrolled oral word association test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003efMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efunctional magnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003efNIRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efunctional near-infrared spectroscopy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP-NIRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eportable fNIRS\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG-PS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eeastern cooperative oncology group-performance status\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCogPCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eperceived cognitive impairments\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCogPCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eperceived cognitive abilities\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAVLT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eauditory verbal learning test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAVLT-DR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAVLT-delayed recall\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTHb\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etotal hemoglobin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efrontal pole\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose\u003c/p\u003e\n\u003ch2\u003eResearch involving Human Participants\u003c/h2\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethical Review Committee for Epidemiological Research of Hiroshima University (25 July 2022 / E2022-0061).\u003c/p\u003e\n\u003ch2\u003eInformed consent\u003c/h2\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003ch2\u003eCompeting Interests:\u003c/h2\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003ch2\u003eEthics approval:\u003c/h2\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethical Review Committee for Epidemiological Research of Hiroshima University (25 July 2022 / E2022-0061).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants signed informed consent regarding publishing their data and photographs.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work was partly supported by the Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society of the Promotion of Science (Grant number JP23K14734).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eConceptualization: Kazuya Saita, Kazuaki Tanabe, Hitoshi Okamura; Data curation: Kazuya Saita, Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Wataru Okamoto, Morihito Okada , Hideki Ohdan; Formal analysis: Kazuya Saita, Kazuaki Tanabe, Fumiko Kaneko, Hitoshi Okamura; Funding acquisition: Kazuya Saita, Hitoshi Okamura; Investigation: Kazuya Saita, Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Fumiko Kaneko, Yukio Mikami, Wataru Okamoto, Morihito Okada, Hideki Ohdan; Methodology: Kazuya Saita, Kazuaki Tanabe, Hitoshi Okamura; Project administration: Hitoshi Okamura; Software: Kazuya Saita, Hitoshi Okamura; Resource: Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Yukio Mikami, Wataru Okamoto, Morihito Okada , Hideki Ohdan; Validation: Kazuya Saita, Fumiko Kaneko; Visualization: Kazuya Saita, Fumiko Kaneko; Writing \u0026ndash; original draft: Kazuya Saita, Kazuaki Tanabe, Hitoshi Okamura; Writing \u0026ndash; review \u0026amp; editing: Kazuya Saita, Kazuaki Tanabe, Yoichi Hamai, Masami Yamauchi, Fumiko Kaneko, Yukio Mikami, Wataru Okamoto, Morihito Okada , Hideki Ohdan, Hitoshi Okamura\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThis work was partly supported by the Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society of the Promotion of Science (Grant number JP23K14734).\u003c/p\u003e\n\u003ch2\u003eData Availability Statement:\u003c/h2\u003e\n\u003cp\u003eThe datasets generated during or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShapiro CL. 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J Psychiatr Res. 2021;140:416\u0026ndash;35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpsychires.2021.06.015\u003c/span\u003e\u003cspan address=\"10.1016/j.jpsychires.2021.06.015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStatements \u0026amp; Declarations\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-survivorship","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcsu","sideBox":"Learn more about [Journal of Cancer Survivorship](https://www.springer.com/journal/11764)","snPcode":"11764","submissionUrl":"https://submission.nature.com/new-submission/11764/3","title":"Journal of Cancer Survivorship","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cancer related cognitive impairment, prefrontal cortex, neuroimaging, cognitive function, near-infrared spectroscopy","lastPublishedDoi":"10.21203/rs.3.rs-5191114/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5191114/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eRisk factors for cancer-related cognitive impairment (CRCI) are diverse; neuroimaging instruments are recommended to complement subjective and objective cognitive assessments. This study aimed to evaluate the feasibility of a multidomain assessment protocol for CRCI in gastrointestinal cancer survivors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eTwenty-four patients with gastrointestinal cancer scheduled for chemotherapy and 24 healthy controls were recruited. The Functional Assessment of Cancer Therapy-cognitive function (FACT-Cog) was used to assess subjective cognitive functions. Objective cognitive function was assessed using the trail-making test, auditory verbal learning test (AVLT), and verbal fluency test. Cerebral hemodynamic changes in the prefrontal cortex were measured using portable functional near-infrared spectroscopy (P-NIRS). Assessments were conducted at baseline and six-month follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThirty-eight participants were included in the analysis. There was a statistically significant difference in AVLT-delayed recall (p=0.002) in the chemotherapy group compared with the healthy control group, \u0026nbsp;but no significant difference in either group for other cognitive assessments. The chemotherapy group exhibited reduced activity in the left frontal pole at six months post-treatment compared to baseline (p=0.018).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eGastrointestinal cancer survivors who receive chemotherapy may exhibit poorer delayed recall of memory functions than healthy individuals. Monitoring prefrontal cortical hemodynamics using P-NIRS during cognitive tasks is feasible for clinical application and understanding CRCI symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplications for Cancer Survivors\u003c/strong\u003e: This multidomain assessments ars translatable to clinical practice and useful for other cancers. Furthermore, It can lead to a deeper understanding of the impact of depressive symptoms and declining motivation on the cognitive function of cancer survivors.\u003c/p\u003e","manuscriptTitle":"Changes in chemotherapy-induced cognitive impairment in gastrointestinal cancer survivors using multidomain assessments: a prospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-08 10:30:03","doi":"10.21203/rs.3.rs-5191114/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-17T07:10:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-10T21:46:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"101111453059649089204866661136936932356","date":"2024-10-06T13:29:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"122437021374797238758181583183380608393","date":"2024-10-05T19:05:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-04T12:14:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-04T09:39:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-04T09:39:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Survivorship","date":"2024-10-02T06:44:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-survivorship","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcsu","sideBox":"Learn more about [Journal of Cancer Survivorship](https://www.springer.com/journal/11764)","snPcode":"11764","submissionUrl":"https://submission.nature.com/new-submission/11764/3","title":"Journal of Cancer Survivorship","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"77a01e6e-8deb-4371-831b-08b1f6e9e66a","owner":[],"postedDate":"November 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-17T16:11:58+00:00","versionOfRecord":{"articleIdentity":"rs-5191114","link":"https://doi.org/10.1007/s11764-025-01759-8","journal":{"identity":"journal-of-cancer-survivorship","isVorOnly":false,"title":"Journal of Cancer Survivorship"},"publishedOn":"2025-02-15 15:57:48","publishedOnDateReadable":"February 15th, 2025"},"versionCreatedAt":"2024-11-08 10:30:03","video":"","vorDoi":"10.1007/s11764-025-01759-8","vorDoiUrl":"https://doi.org/10.1007/s11764-025-01759-8","workflowStages":[]},"version":"v1","identity":"rs-5191114","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5191114","identity":"rs-5191114","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}