結直腸癌病人癌症相關認知障礙與雙重任務走路訓練對其改善之成效探討

Abstract

背景：癌症相關認知功能障礙(Cancer-Related Cognitive Impairment, CRCI)發生率高達70%以上，為接受癌症相關治療過程中常見且感到困擾的症狀，對病人日常生活與生活品質帶來嚴重影響。此研究議題由於過去多著重於乳癌病人、並因症狀多屬輕度，故較其他症狀容易被忽略；然而，於臺灣結直腸癌發生率高、且所使用的化學治療藥物亦與認知功能障礙具高相關性，卻仍缺乏相關研究；此外，亦因影響認知功能的因素眾多，故在介入研究設計上面臨極大挑戰，使得有效介入措施仍未有一致定論。文獻指出雙重任務走路(Dual-task walking, DTW)為身體運動結合認知任務同步執行之訓練，能對認知功能帶來益處，但截至目前，國內外仍未有針對癌症族群介入此訓練對於認知功能改善之成效探討；因此，雙重任務走路介入處置是否能有效改善結直腸癌病人接受化學治療後之認知功能表現仍不得而知。 目的：(1)瞭解結直腸癌病人「正在接受化學治療3~6個月期間」與「完成治療後五年內存活期」兩個不同階段之認知功能現況、因化學治療導致其認知功能下降之差異，以及輕度認知功能障礙發生率。(2)根據目的(1)之研究結果發展與測試12週居家雙重任務走路訓練介入措施，於結直腸癌病人接受化學治療後，改善其認知功能（主觀認知功能、整體客觀認知功能，以及注意力、記憶力、執行功能層面）之成效。 方法：兩階段研究執行期間自2020年9月至2024年5月，於臺北市某兩間醫學中心之大腸直腸外科門診、腫瘤醫學科門診、化學治療室以及住院病房收案。第一階段採量性橫斷性研究設計，以問卷訪談方式，選取年齡40歲（含）以上至75歲、確立診斷為第I-III期手術後正在進行化學治療3~6個月期間或已完成化學治療五年內之結直腸癌病人進行資料收集。第二階段採分層隨機對照試驗研究設計，選取年齡40歲（含）以上至75歲、初診斷為第II-III期、手術後預計接受針劑化學治療之結直腸癌病人為研究對象，於病人至少已接受三次化學治療後（約進行化學治療三個月）依其蒙特利爾認知評估量表測試分數（<24分和≧24分）與年齡（<65歲和≧65歲）進行兩次分層，並採1:1區塊隨機分派(Block randomization)後進行前測。實驗組參與者於完成前測後接受三次面對面衛教、共12週的雙重任務走路訓練，及每週的電話訪談或Line個人群組追蹤；控制組參與者為接受常規照護。成效測量採問卷評量方式，包括主觀與客觀認知功能（注意力、執行功能、記憶力）量表，以及身心症狀困擾（症狀嚴重度、疲倦、憂鬱）程度評估。資料收集時間點共三次，分別為：至少接受三次化學治療後/介入訓練執行前（前測，T0）、12週介入訓練後（第1次後測，T1），以及介入措施完成後12週（第2次後測，T2）。12週介入訓練期間，實驗組與控制組參與者皆給予Fitbit運動手環配戴，以紀錄及比較兩組走路步數之差異。資料分析方法於第一階研究段採複迴歸分析(Multivariable Linear Regression)校正/控制干擾因素後比較「正在接受化學治療」、「已完成化學治療五年內」兩組認知功能之差異。第二階段採廣義估計方程式(Generalized Estimating Equations, GEE)分析雙重任務走路訓練於改善認知功能下降之成效，即實驗組與控制組之主、客觀認知功能的成效差異。 研究結果：第一階段研究共100位參與者納入研究分析，平均年齡為55.76歲、拒絕參與率為37.89%，研究結果為在控制干擾因素（年齡、教育年數、身體功能狀態、症狀嚴重度）後，兩組參與者於主觀認知功能不具顯著性差異；於客觀認知功能部分，「已完成治療組」之整體認知功能、立即記憶、注意力、處理速度、抑制認知干擾能力、語意流暢程度與執行功能表現顯著較「正在接受治療組」差。另外，採蒙特利爾認知評估量表總分26分為切點，顯示與「正在接受治療組」（2位、4.76%）相比，「已完成治療組」（14位、24.14%）有顯著較高比例人數具有輕度認知功能障礙(p = 0.01)。第二階段研究共33位參與者納入研究分析，實驗組17位、平均年齡為56.29歲，控制組16位、平均年齡為56.81歲，研究參與率為76.74%、問卷完成率為84.85%、介入措施完成率為65.20%。治療意向分析法(Intent-to-treat analysis, ITT)之結果顯示，兩組參與者於主觀認知功能表現不具顯著性差異，於客觀認知功能部分，與T0相比，實驗組於T1時之整體認知功能、立即記憶、延遲記憶、注意力與工作記憶的表現較控制組好(Cohen’s d = 0.68~0,89; p < 0.05)。另外，與T0相比，實驗組於T2時之語意流暢度與執行功能表現較控制組好(Cohen’s d = 1.33; p = 0.007)。 結論：已完成化學治療五年內之結直腸癌病人，其整體認知功能、立即記憶、注意力與執行功能將可能受到化學治療影響而較正在接受化學治療的病人表現差。雙重任務走路訓練對於正在接受化學治療之結直腸癌病人的整體認知功能、立即記憶、延遲記憶、注意力與工作記憶具短期介入效果，對語意流暢度與執行功能具3個月之維持效果。未來仍需大樣本數研究證實雙重任務走路訓練之介入成效。

Background: Up to 70% of patients with cancer had reported suffering from cancer-related cognitive impairment (CRCI), which commonly affects attention, executive function, and memory and challenges daily functioning, working ability, and quality of life. Recently, colorectal cancer (CRC) has a high incidence rate in Taiwan and the toxicity of chemotherapy regimens on CRC has been linked to CRCI. Nevertheless, this deleterious effect among patients with CRC is still understudied. Dual-task walking (DTW) combining physical exercise and cognitive tasks training has been suggested to improve cognitive performance. However, there is no study has applied DTW programs to patients with CRC and focused on exploring the effect of DTW training on improving CRCI in this population. Purposes: (1) To describe and compare subjective and objective cognitive functioning in patients with CRC under two different treatment statuses, including active treatment patients undergoing chemotherapy within three to six months, and survivors completed chemotherapy less than five years. (2) To develop and test the effect of 12-week home-based DTW training on improving subjective and objective cognitive function (including attention, executive function, and memory) in patients with CRC treating with chemotherapy. Methods: Data were collected from September 2020 to May 2024. Participants were approached from surgical and oncology clinics, chemotherapy rooms, and inpatients wards in two Taiwanese northern medical centers. In the first phase, a comparative cross-sectional approach was conducted, 100 patients aged ranging 40-75 years with stage I-III CRC undergoing chemotherapy within three to six months or completed adjuvant chemotherapy less than five years were recruited. In the second phase, a stratified randomized control trial based on a total score of the Montreal Cognitive Assessment (MoCA) (<24 VS. ≥24) and age (<65years VS. ≥65years) was conducted. Patients with stage II-III CRC who have completed at least the third chemotherapy infusion were recruited. Individuals in the experimental group received a 12-week training with three-time face-to-face DTW training courses. Individuals in the control group received usual care. The results of cognitive performance were assessed and evaluated at baseline (T0), after 12-week training(T1), and 3 months after training (T2) by a set of questionnaires consisting of a subjective cognitive function scale and the neuropsychological assessment battery assessing attention, executive function, and memory, as well as the Symptom Severity Scale (SSS), the Cancer Fatigue Scales (CFS), and the Center for Epidemiological Studies Depression Scale (CES-D). The difference of cognitive performance between two different treatment statuses was examined using multivariable linear regression controlling CRCI related confounding factors. The effect of DTW training was examined using generalized estimating equations (GEE). Results: In the first phase, 100 participants with a mean age of 55.76 years were recruited. The rejection rate was 37.89%. There was no significant between-group difference in subjective cognitive functioning. The completed treatment group had significantly worse overall cognition, immediate memory, processing speed, attention, ability to inhibit cognitive interference, semantic fluency, and executive functions as comparison with the active treatment group after controlling age, years of education, functional status, and symptom severity. The completed treatment group had significantly higher prevalence rate of mild cognitive impairment as comparison with the active treatment group using MoCA<26 as cut-off point (p=0.01). In the second phase, a total of 33 patients were assigned to the DTW group with a mean age of 56.29 years (n = 17) or the control group with a mean age of 56.81 years (n = 16). The study participation rate was 76.74%. The completion rate of cognitive assessments was 84.85%. Among the participants assigned to DTW group, 65.20% completed the 12-week intervention. Intent-to treat analysis indicated that participants assigned to the DTW group demonstrated significant improvements in overall cognition, attention, immediate memory, delayed memory, and working memory at T1 (Cohen’s d = 0.68~0,89; p < 0.05), as well as semantic fluency and executive functions at T2 (Cohen’s d = 1.33; p = 0.007) than those assigned to the control group. Conclusion: Chemotherapy may negatively affect domains of overall cognition, immediate memory, attention, and executive functions for CRC survivors after the completion of chemotherapy. The DTW training displays short-term treatment effect on improving overall cognition, attention, immediate memory, delayed memory, and working memory, and three-month sustained treatment effect on improving semantic fluency and executive functions. The findings suggest that a larger randomized study to examine the efficacy of DTW is warranted.