運動訓練於肺癌病患肌肉功能、胰島素阻抗、運動能力與生活品質之效果

Abstract

肺癌的年發生與致死率高，其中以非小細胞肺癌（non-small cell lung cancer）居多，占所有肺癌個案的80到85%。患者被診斷出肺癌時，多已近後期。近年來，標靶治療（targeted therapy）因毒性與副作用較低，被用來治療此類患者。隨疾病進展、惡化，持續慢性發炎（chronic inflammation）與胰島素阻抗（insulin resistance），可進一步導致肌肉萎縮（muscle wasting）或伴隨脂肪下降、體重減低、運動能力減弱、日常體能活動受限和惡病質（cachexia），使得肺癌病患者生活品質低落。而非小細胞肺癌患者的運動能力或體能表現，與治療適用性、術後併發症或長期存活率相關。文獻顯示運動可改善乳癌或是綜合癌症族群之癌症相關症狀、運動能力與生活品質，然而罕見於肺癌患者。本研究目的為探討八週運動訓練對肺癌患者之肌肉功能、胰島素阻抗、運動能力、生活品質與其他癌症相關參數的效果。 本研究從門診共徵召24位接受標靶治療之非小細胞肺癌患者（50%男性，平均年齡59.9±7.2歲），將他們隨機分入運動組（n=13）或控制組（n=11）。運動組將接受個別化有氧間歇運動訓練（aerobic interval exercise training），而控制組僅接受一般照護、無運動訓練之介入。運動訓練在物理治療師監測下，每週執行三次，每次約30~40分鐘的跑步機或腳踏車訓練，包含暖身與緩和期，並以最大攝氧量與自覺用力係數（rate of perceived exertion）做為強度指標。有氧間歇運動為高強度（80%最大攝氧量或自覺用力係數15~17）的間歇期與中強度（60%最大攝氧量或自覺用力係數11~13）的主動恢復（active recovery）所組成。每1~2週物理治療師將會依個人狀況調整運動訓練計畫。所有受試者接受兩次評估：基準點（baseline）與八週後追蹤（follow-up）。評估項目包括：右股四頭肌肌力與肌耐力、運動中肌肉氧合狀態（muscle oxygenation）、HOMA-IR（Homeostasis model assessment-insulin resistance）、最大攝氧量（peak oxygen consumption）與生活品質問卷調查；其他癌症相關評估為Ｃ反應蛋白（C-reactive protein）、全身體脂肪與非脂肪組織含量。介入前後，亦利用問卷監測受試者的體能活動與飲食攝取。使用SPSS套裝軟體分析資料，有效顯著水平訂為0.05。以雙因子重複變異數分析（two-way repeated measures analysis of variance）比較兩組在各評估項目的差異，並以皮爾森相關係數檢定運動訓練後運動能力改變的相關因子。 和同年齡、性別與體型之正常人相比，24名受試者的基準點運動能力偏低（平均最大攝氧量預測值百分比為49.1±9.8%），最大攝氧量預測值與運動中肌肉氧合狀態（r=-0.50, p=0.02）、Ｃ反應蛋白（r=-0.53, p=0.02）、呼吸困難（r=-0.55, p=0.01）和體能活動（r=0.44, p=0.02）相關。兩組有相似的基本資料，且基準點評估的任一參數，皆無統計上顯著組間差異。受試者於介入期間維持其一般活動與飲食攝取，有6人因個人因素或治療方法改變而退出本計畫（運動組2人、控制組4人），運動組的運動依從性（adherence）為71.2%。經過八週運動訓練介入後，運動組的最大攝氧量和最大攝氧量預測值百分比分別增加1.6 mi/kg/min和5.3%（p<0.005），且其進步與最大運動時周邊、心臟和呼吸改善有關（所有p=0.001）。運動組的呼吸困難亦顯著下降（p=0.01），疲勞則無組間差異（p=0.30）。運動組受試者的右股四頭肌肌力與肌耐力提高，然運動中肌肉氧合狀態、HOMA-IR、Ｃ反應蛋白、全身體脂肪與非脂肪組織含量於八週後無改變。 正在接受標靶治療非小細胞肺癌患者，即使生活品質與存活率提高，其運動能力和正常人相比仍較低。本研究為第一個探討此類型患者之運動訓練效果的研究。運動組在運動過程中無任何併發症發生，訓練後運動能力增加、呼吸困難症候改善，建議此類患者可接受運動訓練，以增進運動能力和改善症狀。未來需更多大型且長期追蹤研究，做進一步的探討。

Lung cancer with high incidence is the leading cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts about 80 to 85% of all lung cancer cases, and most patients with NSCLC were in advanced stage at diagnosis. Recently, targeted therapy has been widely used to treat this population due to its low toxicity and less side effects. Commonly seen features associated with chronic inflammation and insulin resistance in patients with NSCLC include skeletal muscle wasting with/ or without fat loss, weight loss, decreased exercise capacity, limited physical activity and even cachexia. These might lead to poor quality of life (QOL). Furthermore, exercise capacity or physical performance is associated with treatment indication, post-operative complications or long-term survival. Previous studies suggested exercise could improve cancer-related symptoms, muscle function, exercise capacity and QOL in patients with breast cancer or mixed cancer types. Whether exercise has a positive impact in patients with NSCLC remains unclear. The purpose of this study was to investigate the effect of 8-week exercise training compared with usual care on muscle function, insulin resistance, exercise capacity, QOL and other cancer-related outcomes in patients with NSCLC receiving targeted therapy. Twenty-four outpatients with diagnosis of NSCLC receiving targeted therapy were recruited and randomly assigned into control (n=11) or exercise groups (n=13). Participants in control group received usual care while participants in exercise group underwent individualized aerobic interval exercise training for 8 weeks. The exercise program consisted of treadmill or cycling training, three times a week under supervision of physical therapist. A total time of each exercise session was 30 to 40 minutes including warm up and cool down with bouts of high-intensity interval (80% VO2peak or 15~17 in rate of perceived exertion, RPE) separated by an active recovery at moderate intensity (60% VO2peak or 11~13 in RPE). Physical therapist adjusted exercise program every 1~2 weeks based on participant tolerance. Outcome measures, including muscle strength and endurance of right quadriceps, muscle oxygenation during exercise, homestasis model assessment of insulin resistance (HOMA-IR), peak oxygen consumption (VO2peak) and questionnaire inventory of QOL, were assessed at baseline and 8 weeks after. Other cancer-related outcomes were C-reactive protein (CRP), total body fat and free-fat mass. Physical activity and dietary intake were also monitored by questionnaire. SPSS was used to make group comparisons by two-way repeated measures analysis of variance (ANOVA). Pearson correlation was used to examine the relationship of exercise capacity to other outcome measures. Alpha level was set at 0.05. Twenty-four participants completed the baseline assessment, and relative low exercise capacity was noted compared to normal subjects with same age, gender, and body size (the mean of percentage of predicted VO2peak [pred VO2peak]: 49.1±9.8%). Pred VO2peak was related with muscle oxygenation during exercise (r=-0.50, p=0.02), CRP (r=-0.53, p=0.02), dyspnea (r=-0.55, p=0.01) and physical activity (r=0.44, p=0.02). Participants in control and exercise group had similar basic characteristics, and there was no between-group difference in any outcome measures at baseline. All participants maintained physical activity and dietary intake throughout the study period. Six participants discontinued this study because of personal reasons or medical changes (2 in exercise group and 4 in control group), the exercise adherence was 71.2%. VO2peak and pred VO2peak increased by 1.6 mi/kg/min and 5.3% (p<0.005) respectively after 8-week training, and these improvements were associated with the ameliorations in peripheral, heart and respiratory function during exercise (all p=0.001). Subjects in exercise group significantly reduced their dypnea after 8 weeks (p=0.01) with no between-group difference in fatigue (p=0.30). Their muscle strength and enduranc also increased, however, no changes in muscle oxygenation, HOMA-IR, CRP, total body fat and free-fat mass were found after 8-week intervention. Even with improving QOL and better survival rate, patients with NSCLC receiving targeted therapy still have lower exercise capacity compared to healthy people. This was the first study to investigate the effects of exercise training in such patient population. No adverse event was observed during exercise. Patients following exercise training had improvement in exercise capacity and ameliorations in dyspnea. Exercise training is recommended for this population to improve exercise capacity and normalized symptoms. Further studies with large sample size and long-term follow-ups are needed.