【摘要】：背景：隨著新藥的開發(fā)和治療手段的規(guī)范化,腫瘤相關性嘔吐、疼痛等逐步得到了有效地處理,癌因性疲乏(the cancer-related fatigue,CRF)逐漸成為影響患者生存質量的最主要因素,它對患者生活及病情的康復都有不利影響,越來越多的醫(yī)家開始關注并致力改善此病。CRF不同于傳統(tǒng)意義的疾病概念,它在各種類型、各種年齡段的癌癥患者的各個階段普遍存在,甚至長期存在于無瘤幸存者中,卻無客觀指標以資診斷。它是一種復雜的、多維度個體性主觀體驗,不僅與腫瘤相關,與患者生理、精神、心理、社會文化背景等諸多方面均有相關,具有明顯的個體差異性,其病因、病機復雜,所以治療往往需要個體化和綜合治療的模式,現代醫(yī)學缺乏有效的治療藥物和手段。而中醫(yī)在治療疾病時注重從整體出發(fā),遵循辨證論治的原則,對疲乏癥候群能更全面的把握及治療,挖掘、整理中醫(yī)藥診治CRF有重要的意義。目的：理論研究目的：通過搜索、整理古今文獻中有關于CRF的論述,總結歸納相對應的中醫(yī)病名、病因病機、診斷、治療及調攝等內容。并從理論上探討健脾益腎法治療中晚期大腸癌CRF的意義與價值。臨床研究目的：觀察中晚期大腸癌患者CRF與生存質量、證候積分、卡氏評分、T淋巴細胞亞群、NK細胞、睪酮、甲狀腺功能、皮質醇的相關性。觀察健脾益腎法對研究對象疲乏、證候群、卡氏評分、體重、T淋巴細胞亞群、NK細胞、睪酮、甲狀腺功能、皮質醇的影響,進一步探討健脾益腎法治療中晚期大腸癌患者CRF的療效及機制。方法：理論研究方法：以“癌因性疲乏”為關鍵詞,在《中國知網期刊全文數據庫》搜索中西醫(yī)關于CRF論治,再以中醫(yī)相關病名為關鍵詞,在《中華醫(yī)典》搜索中醫(yī)古籍中可能與癌因性疲乏的相關論述,歸納、總結CRF的中醫(yī)病因、病機、治療、調攝等內容。臨床研究方法：選取2011年12月至2015年6月于廣東省第二中醫(yī)院住院及門診就診且符合納入與排除標準的中晚期大腸癌合并CRF患者76例為研究對象。采用隨機數字表法將其分為治療組和對照組,各38例。兩組患者均行FOLFOX6化療,同時,治療組患者全程輔助健脾益腎方。收集干預前生存質量評估量表、干預前后疲乏量表、癥狀積分量表,卡氏評分,抽取外周血檢查干預前后T淋巴細胞亞群、NK細胞、睪酮、甲狀腺功能、皮質醇。建立數據庫,進行統(tǒng)計分析。統(tǒng)計方法：采用SPSS21.0軟件包建立數據庫,進行數據錄入。所有計量資料以均值加減標準差(x±s)表示,兩組間均值比較采用獨立樣本t/t’檢驗,干預前后自身對照均值比較,采用配對t檢驗；所有計數資料均以頻數(f)和百分率或構成比(P)表示,無序分類資料采用Pearson卡方檢驗(x2),四格表資料采用Fisher確切概率法,小樣本等級資料以平均秩次表示(R),進行兩獨立樣本秩和Mann-Whitney U檢驗；兩計量變量間相關性分析,采用Pearson相關系數(r)表示,對相關系數進行t檢驗,對健脾益腎法適合人群進行多重對應(最優(yōu)尺度)分析。α=0.05.結果：理論研究結果：根據CRF特點及患者表現不同側重,中醫(yī)與之相對應的病名有“虛勞”、“百合病”、“臟躁”、“郁證”、“健忘”等。以上述病名搜索于《中華醫(yī)典》,結果顯示CRF的病因有先天不足、飲食失調、勞逸失常、情志內傷、病后失調、外感六淫等諸多因素,概而言之,不外先天、后天兩端。病機為正虛邪戀,臟腑氣血陰陽虧虛。治療上包括扶正補虛、祛邪逐寇、療程當長、雜合而治等原則和方法。臨床研究結果：干預前研究結果：疲乏的總積分與生存質量量表中軀體功能、角色功能、認知功能、情緒功能、社會功能、總健康狀況呈負相關(P0.05),而與疼痛、疲勞、失眠、食欲喪失、呈正相關(P0.05),與氣促、惡心嘔吐、便秘、腹瀉、經濟困難無顯著相關性(P0.05)。行為、情感、感覺、認知各維度與生存質量各領域相關性與疲乏總分一致。疲乏總評分與男性睪酮呈負相關(P0.01),與女性睪酮無相關性。疲乏總評分與皮質醇呈負相關(P0.05)。疲乏總評分與CD4+、CD4+/CD8+呈負相關(P0.05),與CD8+呈正相關(P0.05),而與CD3+、NK無顯著性相關(P0.05)。疲乏總評分與TSH呈正相關(P0.05),與FT3、FT4無顯著性相關(P0.05)。疲乏評分與證候積分、卡氏評分呈正相關(P0.05)。疲乏療效評價：與對照組比較,治療組疲乏總評分、行為維度、感覺維度、認知維度顯著降低(P0.05),情感維度無顯著性差異(P0.05)；治療組疲乏總評分差、行為維度差、認知維度差顯著性降低(P0.05),情感維度差、感覺維度差無顯著性差異(P0.05)。與干預前對比,治療組疲乏總評分、行為維度、感覺維度、認知維度顯著性降低(P0.01),情感維度無顯著性差異(P0.05)；對照組疲乏總評分、行為維度、情感維度、感覺維度無顯著性差異(P0.05),認知維度顯著性升高(P0.05)。治療組35例中顯效2例、有效20例、無效13例,有效率62.86%；對照組中顯效1例、有效6例、無效27例,有效率20.59%。治療組療效明顯優(yōu)于對照組(P0.05)。治療組干預前輕度疲乏患者有6例,干預后增加到14例,中度疲乏患者由干預前23例減少到干預后的18例,干預前6例重度疲勞患者干預后減少到3例,干預后治療組患者疲乏程度減輕；對照組干預前輕度疲乏患者有5例,干預后減少到2例,干預前中度疲乏患者22例,干預后仍為22例,干預前7例重度疲乏患者增加到干預后的10例,對照組干預后疲乏分級無顯著性差異。兩組對比,治療組疲乏等級緩解明顯優(yōu)于對照組(P0.05)。證候療效評價：與對照組對比,治療組證候總分、神疲乏力、頭暈目眩、耳鳴耳聾、形體消瘦、失眠、食少納呆、腹脹、大便溏泄、便秘、腰酸、舌脈評分顯著性降低(P0.05),惡心嘔吐、腹痛、膝軟無顯著性差異(P0.05)；干預前后差值中證候總分、神疲乏力、頭暈目眩、耳鳴耳聾、形體消瘦、失眠、食少納呆、腹脹、大便溏泄、腰酸、舌脈積分顯著性降低(P0.05),惡心嘔吐、腹痛、便秘、膝軟無顯著性差異(P0.05)。與干預前對比,治療組中證候總分、神疲乏力、頭暈目眩、形體消瘦、失眠、食少納呆、腹脹、腹痛、大便溏泄、便秘積分顯著降低(P0.05),耳鳴耳聾、惡心嘔吐、腰酸、膝軟、舌脈無顯著性差異(P0.05)；對照組中神疲乏力、耳鳴耳聾、腹痛、便秘、舌脈積分顯著升高(P0.05),證候總分、頭暈目眩、形體消瘦、失眠、食少納呆、惡心嘔吐、腹脹、大便溏泄、腰酸、膝軟積分無顯著性差異(P0.05)。生存狀態(tài)療效評價：與對照組對比,治療組KPS評分有顯著性增加(P0.01),干預前后KPS評分差無顯著性變化(P0.05)；與干預前對比,治療組無顯著性差異(P0.05),對照組KPS評分顯著性降低(P0.01)。平均體重變化評價：與對照組對比,治療組體重無顯著性差異(P0.05),干預前后體重差有顯著性差異(P0.01),治療組體重下降少；與干預前對比,治療組體重增加(P0.01),對照組體重無明顯變化(P0.05)。睪酮評價：與對照組對比,治療組男、女睪酮濃度、濃度前后差均無顯著性差異(P0.05)；與干預前對比,治療組男、女均無顯著性差異(P0.05);對照組男性睪酮濃度顯著降低(P0.05),對照組女性無顯著性差異(P0.05)。免疫功能評價：與對照組比較,治療組CD3+、CD4+、NK顯著升高(P0.05),CD8+、CD4+/CD8+無顯著性差異；干預前后CD4+差值、NK差值有顯著性差異(P0.05),CD3+差、CD8+差、CD4+/CD8+差無顯著性差異(P0.05)。與干預前對比,治療組CD3+、CD4+無顯著性差異(P均0.05),CD8+顯著下降、CD4+/CD8+顯著升高、NK顯著升高(P0.05)；對照組CD3+、CD8+、CD4+/CD8+、NK無顯著性差異(P0.05),CD4+顯著下降(P0.05)。皮質醇評價：與對照組對比,治療組皮質醇濃度、濃度前后差無顯著性差異(P0.05)。與干預前對比,治療組無顯著性差異(P0.05),對照組皮質醇濃度顯著降低(P0.05))。結論：CRF從各方面影響中晚期大腸癌患者的生存質量,疼痛、疲勞、失眠、食欲喪失等不適癥狀導致中晚期大腸癌患者生存質量下降的同時,也使患者出現CRF。而氣促、惡心嘔吐、便秘、腹瀉、經濟困難等癥狀,或因出現頻率少,或因對癥治療效果好,對CRF影響不大。患者證候積分越高,體力狀態(tài)越低,疲乏越重。CRF與皮質醇分泌降低、甲狀腺功能低下、免疫功能紊亂相關,在男性患者,CRF與低睪酮血癥相關。健脾益腎法可緩解化療期間中晚期大腸癌患者疲乏,主要對行為維度、感覺維度、認知維度有效,對情感維度無明顯療效�？删徑饣熁颊哒w癥狀,主要對神疲乏力、頭暈目眩、耳鳴耳聾、形體消瘦、失眠、食少納呆、腹脹、大便溏泄、便秘、腰酸、舌脈有效,對惡心嘔吐、腹痛、膝軟等癥狀無明顯療效。有改善化療患者體力狀態(tài)的作用。有增加化療患者體重的作用。對男性患者化療后睪酮損傷有保護作用。對化療引起的甲狀腺功能損傷有保護作用。有提高化療患者免疫功能的作用。中晚期大腸癌患者脾腎虧虛多見,健脾益腎法對行FOLFOX6化療的中晚期大腸癌患者癌因性疲乏、證候積分及生存狀態(tài)的均有改善作用。其可能的機制與調節(jié)血清皮質醇、睪酮、免疫和甲狀腺功能相關。在中晚期大腸癌患者癌因性疲乏治療中健脾益腎法有主導性地位,但仍提倡綜合治療的模式。
[Abstract]:BACKGROUND: With the development of new drugs and the standardization of treatment methods, cancer-related vomiting and pain have been effectively treated. Cancer-related fatigue (CRF) has gradually become the most important factor affecting the quality of life of patients. It has a negative impact on the life of patients and the rehabilitation of the disease. More and more doctors are working on it. CRF is a complex, multi-dimensional, individualized subjective experience that is not only associated with cancer, but also with cancer. It is related to many aspects, such as physiology, spirit, psychology, social and cultural background of patients, and has obvious individual differences. Its etiology and pathogenesis are complex, so treatment often needs individualized and comprehensive treatment mode. Modern medicine lacks effective treatment drugs and means. The principle of treatment is of great significance to comprehensively grasp and treat fatigue syndrome, excavate and sort out the treatment and treatment of CRF by TCM. Objective: Theoretical research purposes: Through searching, sorting out the discussion about CRF in ancient and modern literature, summarizing the corresponding TCM disease name, etiology and pathogenesis, diagnosis, treatment and adjustment. Objective: To observe the correlation between CRF and quality of life, syndrome score, Karl's score, T lymphocyte subsets, NK cells, testosterone, thyroid function and cortisol in patients with advanced colorectal cancer. Objective:To explore the therapeutic effect and mechanism of invigorating spleen and tonifying kidney therapy on CRF in patients with advanced colorectal cancer.Methods: Theoretical research method: Using "cancer-related fatigue" as the key word, searching the Chinese and Western medicine on the treatment of CRF in the "China Knowledge Network Journal Full Text Database" in the "China Knowledge Network Journal Full Text Database". Then, with the name of TCM-related diseases as the key words, this paper searches the ancient books of TCM for the discussion of possible cancer-related fatigue, summarizes the TCM etiology, pathogenesis, treatment and intervention of CRF. 76 patients with CRF complicated with advanced colorectal cancer were divided into treatment group and control group by random number table method, 38 cases in each group. Tables, Karl's score, T lymphocyte subsets, NK cells, testosterone, thyroid function, cortisol before and after intervention were collected and analyzed statistically. Statistical methods: SPSS21.0 software package was used to establish a database for data entry. All measurement data were expressed as mean plus or minus standard deviation (x + s). The mean values between the two groups were compared. The independent sample t/t'test was used to compare the self-control mean before and after intervention, and the paired t-test was used to compare the self-control mean before and after intervention. Two independent sample rank and Mann-Whitney U test; correlation analysis between two measurement variables, using Pearson correlation coefficient (r) expression, correlation coefficient T test, multiple corresponding (optimal scale) analysis of the method for invigorating spleen and benefiting kidney for the population. The corresponding names of the diseases are "exhaustion", "lily disease", "dirty impetuosity", "depression syndrome", "forgetfulness" and so on. The above-mentioned names were searched in the "Chinese Medical Code". The results showed that the causes of CRF were congenital deficiency, eating disorders, maladjustment of work and rest, emotional internal injury, disorders after illness, six exogenous factors and so on. Clinical research results: Pre-intervention results: Total scores of fatigue and the physical function, role function, cognitive function, emotional function, social function, total health status in the quality of life scale were presented. Negative correlation (P 0.05), and pain, fatigue, insomnia, loss of appetite, was positively correlated (P 0.05), and shortness of breath, nausea and vomiting, constipation, diarrhea, economic difficulties were not significantly correlated (P 0.05). Behavior, emotion, sensation, cognitive dimensions and quality of life in all areas of correlation and fatigue total score was consistent. Total fatigue score was negatively correlated with cortisol (P 0.05). Total fatigue score was negatively correlated with CD4 +, CD4 + / CD8 +, and positively correlated with CD8 + (P 0.05), but not with CD3 +, NK (P 0.05). Total fatigue score was positively correlated with TSH (P 0.05), but not with FT3 and FT4 (P 0.05). There was a positive correlation between the scores (P 0.05). Fatigue efficacy evaluation: Compared with the control group, the total score, behavior dimension, sensory dimension and cognitive dimension of fatigue in the treatment group were significantly lower (P 0.05), but there was no significant difference in emotional dimension (P 0.05); the total score of fatigue in the treatment group was poor, behavior dimension was poor, cognitive dimension was significantly lower (P 0.05), emotional dimension was poor, and sensory dimension was significantly lower (P 0.05). There was no significant difference (P 0.05). Compared with pre-intervention, the total score of fatigue, behavioral dimension, sensory dimension and cognitive dimension decreased significantly (P 0.01), while the emotional dimension had no significant difference (P 0.05); the total score of fatigue, behavioral dimension, emotional dimension, sensory dimension had no significant difference (P 0.05) in the control group, and the cognitive dimension increased significantly (P 0.05). In the treatment group, 2 cases were markedly effective, 20 cases were effective, 13 cases were ineffective, the effective rate was 62.86%; in the control group, 1 case was markedly effective, 6 cases were effective, 27 cases were ineffective, the effective rate was 20.59%. In the control group, there were 5 patients with mild fatigue before intervention, 2 patients with mild fatigue after intervention, 22 patients with moderate fatigue before intervention, 22 patients with moderate fatigue after intervention, 10 patients with severe fatigue before intervention and 10 patients with dry control group. Compared with the control group, the total score of syndrome, fatigue, dizziness, tinnitus and deafness, body emaciation, insomnia, anorexia, abdominal distention, fecal discharge, constipation, lumbar acid, tongue and pulse scores decreased significantly in the treatment group. Low (P 0.05), nausea and vomiting, abdominal pain, knee weakness had no significant difference (P 0.05); before and after the intervention, the total score of syndromes, fatigue, dizziness, tinnitus and deafness, body emaciation, insomnia, anorexia, abdominal distention, fecal discharge, lumbar acid, tongue and pulse integral significantly decreased (P 0.05), nausea and vomiting, abdominal pain, constipation, knee weakness had no significant difference (P 0.05). The total score of syndromes, fatigue, dizziness, weight loss, insomnia, food intolerance, abdominal distention, abdominal pain, fecal discharge, constipation, tinnitus and deafness, nausea and vomiting, lumbar acid, knee weakness, tongue and pulse were significantly lower in the treatment group (P 0.05), but no significant difference was found in the control group (P 0.05). The total score of syndrome, dizziness, emaciation, insomnia, low intake of food, nausea and vomiting, abdominal distention, fecal discharge, lumbar acid, knee soft score had no significant difference (P Compared with the control group, there was no significant difference in body weight between the treatment group and the control group (P 0.05). The KPS score of the control group decreased significantly (P 0.01). The average weight change evaluation: Compared with the control group, there was no significant difference in body weight between the treatment group and the control group (P 0.05). Testosterone evaluation: Compared with the control group, there was no significant difference in the concentration of testosterone between the treatment group and the control group (P 0.05); compared with the pre-intervention, there was no significant difference in the concentration of testosterone between the treatment group and the control group (P 0.05); the concentration of testosterone in the control group decreased significantly (P 0.05), and there was no significant difference in the control group (P 0.05). (P 0.05). Immune function evaluation: Compared with the control group, CD3 +, CD4 +, NK increased significantly (P 0.05), CD8 +, CD4 + / CD8 + had no significant difference; before and after intervention, CD4 + difference, NK difference had significant difference (P 0.05), CD3 + difference, CD8 + difference, CD4 + / CD8 + difference had no significant difference (P 0.05). Cortisol evaluation: Compared with the control group, the cortisol concentration of the treatment group, before and after the difference was not significant (P 0.05). Compared with the control group, there was no significant difference in the treatment group (P 0.05). Conclusion: CRF affects the quality of life, pain, fatigue, insomnia, loss of appetite and other discomfort symptoms of patients with advanced colorectal cancer in various aspects, which leads to the decline of quality of life in patients with advanced colorectal cancer, at the same time, it also causes CRF in patients with shortness of breath, nausea and vomiting, constipation, diarrhea, economic difficulties and other symptoms. CRF is associated with decreased cortisol secretion, hypothyroidism, and immune dysfunction. In male patients, CRF is associated with hypotestosteronemia. Spleen-invigorating and kidney-nourishing therapy can alleviate the late stage of chemotherapy. Fatigue in patients with colorectal cancer is mainly effective in behavioral, sensory and cognitive dimensions, but has no obvious effect on emotional dimensions. It can relieve the overall symptoms of chemotherapy patients, mainly on mental fatigue, dizziness, tinnitus and deafness, body emaciation, insomnia, anorexia, abdominal distention, fecal discharge, constipation, lumbar acid, tongue and pulse effective, nausea and vomiting, abdominal pain, knee weakness, etc. It can improve the physical condition of patients with chemotherapy, increase the weight of patients with chemotherapy, protect the testosterone damage of male patients after chemotherapy, protect the thyroid function damage caused by chemotherapy, and improve the immune function of patients with chemotherapy. Spleen-tonifying kidney therapy can improve the cancer-related fatigue, syndrome scores and survival status of patients with advanced colorectal cancer undergoing FOLFOX6 chemotherapy. Its possible mechanism is related to the regulation of serum cortisol, testosterone, immunity and thyroid function. Advocate the mode of comprehensive treatment.
【學位授予單位】：廣州中醫(yī)藥大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R735.34

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