摘要
肺癌与肠癌的发病率、死亡率分别居恶性肿瘤第一位及第三位。虽然以上两种肿瘤在近些年的研究不断深入,新的药物层出不穷,但疗效仍不尽如人意。中医药参与的癌症综合治疗是我国恶性肿瘤治疗的重要组成部分。中医治疗肿瘤是一个复杂性的干预过程,在微观上其作用呈现多靶点、多途径,在宏观上其强调“同病异治”、“异病同治”的个体化诊疗模式,可选择诸如中药汤剂、中成药、中药注射液、中药外敷、中药泡洗、针灸等综合治疗方法。但是既往研究中多采用单一治疗手段进行观察,无法全面反映中医药的作用特点。本文在分为中医药对炎性微环境的作用机制探讨及临床病例回顾分析两部分,力图从微观与宏观两个方面揭示中医药治疗恶性肿瘤的作用规律,为优化临床治疗方案并进一步深入研究提供可靠的依据。
一.实验研究
目的观察中药肺瘤平膏干预肿瘤炎性微环境重要通路TNF-α-NF-κ B-Snail的作用靶点和效应机制。方法观察肺瘤平膏、CTX及肺瘤平膏+CTX对Lewis肺癌小鼠的抑瘤作用,并用免疫组化的方法检测肺癌组织中E-cadherin、N-cadherin、NF-KB的表达,采用ELISA法检测炎症微环境中IL-1β、IL-6及TNF-α的表达。
结果
1.可见各组小鼠的体重较造模前订均有不同程度的增加,其中空白组最为显著,模型组变化最小,肺瘤平膏、CTX及肺瘤平膏+CTX对Lewis肺癌移植瘤均有一定的抑制作用(P<0.05),各组小鼠肿瘤瘤重：如下肺瘤平膏加CTX组瘤重CTX组>肺瘤平膏组。
2. E-cadherin蛋白：与模型组比较,肺瘤平膏组与肺瘤平膏+CTX E-cadherin表达呈明显提高,肺瘤平膏VS模型组(P<0.05),肺瘤平膏+CTX vs模型组(P<0.01),但治疗组间差异无统计学意义,肺瘤平膏+CTX组有提高趋势(P>0.0083)*。
3. N-cadherin:肺瘤平膏及肺瘤平膏+CTX组N-cadherin蛋白下调明显(P<0.01),两者间比较未见明显差异(P>0.0083)*。
4.NF-KB:与模型组比较,肺瘤平膏组、CTX组及肺瘤平膏+CTX组N-cadherin蛋白呈不同程度的下调,肺瘤平膏+CTX VS模型组(P<0.01),肺瘤平膏vs模型组(P<0.01),CTX vs模型组(P<0.05),治疗组间比较差异无统计学意义,肺瘤平膏+CTX有更强的降低趋势,但无统计学意义(P>0.0083)*。
5.IL-1β：与模型组比较,肺瘤平膏组、CTX组及肺瘤平膏+CTX均有下调小鼠血清中IL-1β含量的作用(P<0.05)；肺瘤平膏+CTX组有更加明显的下调趋势,但差异无统计学意义(P>0.05)。
6.IL-6：与模型组比较,肺瘤平膏组、CTX组及肺瘤平膏+CTX均有下调小鼠血清中IL-6含量的作用(P<0.05)；肺瘤平膏+CTX组有更加明显的下调趋势,但差异无统计学意义(P>0.05)。
7.TNF-α:与模型组比较,肺瘤平膏组、CTX组及肺瘤平膏+CTX的小鼠血.清中TNF-α含量均显著降低(P<0.01),肺瘤平膏+CTX组有更加明显的下调趋势,但差异无统计学意义(P>0.05)。
二.临床病例回顾分析
目的对本院住院治疗的IVA及IVB期的大肠癌的总体病例进行回顾分析,并观察中西医结合与纯中医治疗的比较,以及前六年与近六年治疗的比较,为制定更为合理的晚期大肠癌中医及中西医治疗方案提供有益资料。
方法本研究试图通过回顾近十二年(2000.1.1-2011.12.31)我科中医药参与治疗的ⅣA-ⅣB期大肠癌患者住院病例,对比分析近六年(2006-2011)与前六年(2000-2005)、中医治疗组与中西医结合组病例的一般情况、治疗方案,近、远期疗效、卫生经济学指标的变化。
结果
1.近六年治疗晚期大肠癌患者有更高的总有效率为35.14%,前六年患者有更高的疾病稳定率为49.02%(P<0.05)。但两者肿瘤控制率并未见显著差异(P>0.05)。近六年患者卡氏评分提高率略高于前六年,29.63%vs28.00%(P<0.05),前六年患者卡氏评分稳定率则明显高于近六年60.00%vs36.11%(P<0.05)。近六年患者体重增高率高于前六年35.63%vs22.37%(P<0.05),体重稳定率前六年高于近六年47.37%vs45.98%(P<0.05)。近六年中位生存时间与前六年比较未见统计学差异,23.5个月VS19个月(P>0.05)。前六年组1年、2年及3年生存率分别是75.81%、43.55%及19.35%,近六年1年、2年及3年生存率分别是84.61%、52.56%及20.51%,但也未见统计学差异(P>0.05)。前六年与近六年疾病进展时间为6个月和11个月,两者间有显著差异(P<0.05),表明近六年比前六年中位TTP有明显改善。近六年比前六年费用效果比更好。
2.中西医组总有效率高于中医组41.46%vs6.67%(P<0.05),中西医组肿瘤控制率也高于中医组76.42%vs62.22%(P<0.05),中医组稳定率高于中西医组55.56%vs34.96%(P<0.05)。中西医组卡氏评分提高率、稳定率明显高于中医组33.61%vs22.09,51.64%vs41.86%(P<0.05),体重提高率及稳定率中西医组优于中医组37.50%vs15.52％,47.12%vs45.76%,(P<0.05)。中西医组与中医组中位生存时间24个月vs19个月,未见显著差异(P>0.05),1年、2年、3年生存率也未见差异83.95%vs76.27%,50.61%vs40.68%,19.75vs16.95%(P>0.05)。疾病进展时间TTP：中西医组优于中医组10个月vs6个月(P<0.05)。中医组患者平均住院日更短(P<0.05),但中西医结合组费用效果比更好。
3.COX回归分析显示肝转移为预后不良因素,有肝转移的患者死亡风险为无肝转移患者的1.473倍(HR=1.473)；中西医结合治疗为TTP预后有利因素,中西医结合治疗的进展风险低于中医组,进展风险为中医组的40.7%。
三.结论：
1.中药肺瘤平膏在肿瘤治疗中作用突出,改善肿瘤炎性微环境中TNF-α-NF-κ B-Snail通路很可能是其内在作用机制。
2.本研究证明中成药肺瘤平膏可能通过抑制肿瘤炎性微环境中TNF-α-NF-κ B-Snail通路关键指标如IL-6、IL-β、TNF-α等炎性因子,并上调E-cadherin,下调N-cadherin及NF-KB而预防EMT发生而,从而间接发挥其抗肿瘤复发转移的作用。
3.中药肺瘤平膏在抑制肿瘤生长,降低化疗毒副作用,改善生活质量方而作用明显。
4.以上作用在中西医结合治疗时(肺瘤平膏+CTX)有更强作用的趋势。
5.总体上我科近12年收治入院的晚期(IVA、IVB)大肠癌病例基本符合目前国际流行病学变化趋势,脾肾阳虚为最为常见的辨证类型,所用病例中医治疗率100%,经COX回归分析,肝转移是OS不利的预后因素,中西医结合治疗是对TTP的有利因素。
6.按纳入治疗时间分组,近六年组化疗使用更为普遍,使患者拥有更好的肿瘤控制、更高的生活质量、更长的疾病进展时间,同时还带来了较少的住院天数、更低的住院总费用和更好的费用效果比,但是前六患者拥有更好的肿瘤稳定率,生活质量稳定率及与近六年组同样的总生存时间。
7.按治疗方式分组,中西医结合治疗组达到了更好的总有效率和肿瘤控制率,更好的疾病进展时间和更经济的治疗。但是中医组具有更多的中医治疗方式、更高的肿瘤稳定率、更少的住院天数及同样的生存时间。
The morbidity and mortality of lung and colon cancers are among the top of all malignant cancers. It is estimated that, the number of medicines on it will be more in the world than before. However,a lot of medicines didn't play an important role in the treatment of them,So a lot of people are searching for new treatment of them. TCM plays an very important role in the treatment of lung and Colon cancer in China. In fact, in the treatment of tumor,TCM emphasizes on determination of treatment based in pathogenesis obtained through different symptoms and signs. Parenteral solution Chinese patent medicine and medicinal broth, can be used for treatment of lung and Colon cancer according to the patient's syndrome and stage of disease.It is sad to say that, most studies assessed effect of single drug or treatment because of limitation of randomized controlled trial. Characteristic of TCM treatment based in pathogenesis obtained through differentiation of symptoms and signs,has not been displayed. This study focused on tow feilds, one is effective influence of Traditional Chinese Medicine (TCM) on inflammatory microenviroment, another is the retrospective study of involvement of TCM in treating advanced colorectal cancer (IVA、IVB).We further investigated the molecular mechanism of inflammatory microenviroment and the effective influence of Traditional Chinese Medicine (TCM) on it.And we also attempted to reveal the trends of TCM treatment of advanced colorectal cancer as well as to provid the useful information on standardization of clinical treatment and improvement the curative effect.
Part Ⅰ Experimental aspects
1Experiment study in vivo
Object To observe the the major pathway of TNF-α-NF-κ B-Snail of inflammatory microenvironment's reaction of Fei Liu Ping sirupu and study its molecular mechanism.
Method To observe the inhibition of Feiliuping sirupu、CTX and Feiliuping sirupu+CTX function on Lewis lung cancer transplantation tumor. The expression of E-cadherin、N-cadherin protein, NF-KB of tumor tissue was detected by immunohistochemical method, and the expression of IL-1β、IL-6and TNF-α was measured by ELISA.
Result
1. Feiliuping sirupu obviously inhibited the growth of the transplantation tumor of Lewis lung cancer.The inhibitory rate of Feiliuping sirupu+CTX、CTX and Feiliuping sirupu were83.25%,64.10%and38.83%.
2. E-cadherin:The expression of E-cadherin in tunmor that treated by feiliuping sirupu and feiliuping sirupu+CTX increased more significantly than that in model, feiliuping sirupu+CTX vs model (P<0.01), feiliuping sirupu+CTX vs model (P<0.05),and there was no significant difference in the three treatment groups*,however, there was a stronger trend in feiliuping sirupu+CTX group (P>0.0083)*.
3. N-cadherin:The expression of N-cadherin in tunmor that treated by feiliuping sirupu and feiliuping sirupu+CTX decreased more significantly than that in model (P<0.01). There was no significant difference between each other (P>0.0083)
4. NF-KB:The expression of NF-KB in tumor that treated by feiliuping sirupu CTX and feiliuping sirupu+CTX decreased more significantly than that in model, feiliuping sirupu+CTX vs model (P<0.01),feiliuping sirupu vs model (P<0.01)、CTX vs model (P<0.05).There was no significant difference in the three treatment groups*.However there was a stronger trend in feiliuping simpu+CTX group (P>0.0083)
5. IL-1β:The expression of IL-1β in blood that treated by feiliuping sirupu CTX and feiliuping sirupu+CTX decreased more significantly than that in model (P<0.05).And it was with no significant difference compared with each other*, but there was a stronger trend in feiliuping sirupu+CTX group (P>0.05)
6. IL-6:The expression of IL-6in blood that treated by feiliuping sirupu、CTX and feiliuping sirupu+CTX decreased more significantly than that in models (P<0.05).And there was no significant difference compared with each other*,but eiliuping sirupu+CTX might be better (P>0.05)
7. TNF-α:The expression of TNF-a in blood that treated by feiliuping sirupu、CTX and feiliuping sirupu+CTX decreased more significantly than that in models (P<0.05).And there was no significant difference compared with each other*, but eiliuping sirupu+CTX might be better (P>0.05)
Part Ⅱ Clinical research
Purpose This study attempts to recall advanced CRC (IVA、IVB) patient medical records participated in the treatment of TCM in our department of Oncology in the last decade (2000.1.1-2011.12.31). So We can provide reliable clinical data for formulating better therapeutic regimen of advanced CRC.
Method This study wants to analyze medical records in the basic situation of case treatment program, short-term and long-term effect, and changes in economic indicators, between in the past six years (2006-2011) and the first six years (2000-2005), between TCM treatment and integrated traditional chinese and western medicine treatment. This study also attempts to reveal the trends of TCM treatment of advanced CRC, as well as to provide the useful information on standardization of clinical treatment and improvement the curative effect.
Result
1.In the past six years, the treatment of advanced colorectal cancer patients had a higher efficiency,and the response rate was35.14%, while in the first six years, the patients had a higher stable disease rate of49.02%(P<0.05). However, both group's disease control rate had no significant difference (P>0.05). The Karnofsky scores of patients in the past six years with improvement were higher than the patients in first six years,29.63%vs28.00%(P<0.05), in the first six years, the patients'Karnofsky stable rate was significantly higher than the past six years,60.00%vs36.11%(P<0.05). Patients'weight increase rate was higher than the patients in the first six years35.63%vs22.37%(P<0.05). In the fiest six years,the weight stable rates was higher than the past six years,47.37%vs45.98%(P<0.05). The median survival time of past six years compared with the first six years has no significant difference,23.5VS19months(P>0.05). The1,2and3year survival rate of patients in the first6years were75.81%,43.55%and19.35%, while in the past six years were84.61%,52.56%and20.51%, but there are no significant difference (P>0.05). The time to progress was6months in the first6years while11months in the past years, and there is a significant difference (P<0.05), indicating that the median TTP is significantly improved in the past6years. The cost-effectiveness ratio of past six years is better than that of the first6years.
2. The integrated treatment group's response rate and disease control rate were significantly higher than the TCM group,41.46%vs6.67%,76.42%vs62.22%(P <0.05). The stable rates of Chinese Medicine group were higher than that of integrated treatment group,55.56%vs34.96%(P<0.05). The integrated treatment group's Karnofsky improve rate and stable rate were significantly higher than the TCM group,33.61%vs22.09,51.64%vs41.86%(P<0.05). The integrated treatment group's weight increase rate and stable rate were higher than the TCM group,37.50%vs15.52%,47.12%vs45.76%,(P<0.05).The median OS of integrated treatment group compared with the TCM group had no significant difference,24VS19months(P>0.05),and the tow groups'1year,2years,3-year survival rate was no difference either,83.95%vs76.27%50.61%vs40.68%,19.75vs16.95%. The time to progress of integrated treatment group was10months while the TCM group was6months, and there was a significant difference (P<0.05),TCM group with an average length of stay was shorter(P<0.05), but the cost-effectiveness ratio of integrative medicine group was better.
3. The COX regression analysis showed that the liver metastases was poor prognostic factors, The risk of death of patients with liver metastasis was1.473times more than patients with no liver metastasis (HR=1.473);integrated treatment was good prognostic factors for TTP, and the risk of progression of integrated treatment group was lower than the TCM group.
Conclusion
1. In the tumor treatment of Traditional Chinese Medicine, the function is outstanding, one of its inherent function mechanism may change the major pathway of TNF-α-NF-κ B-Snail of inflammatory microenviroment in tumor patients.
2. This study demonstrates that the Feiliuping sirupu may inhibit the major pathway of TNF-α-NF-κ B-Snail of tumor inflammatory microenvironment of IL-6, IL-1β, TNF-α and other inflammatory factors, increase E-cadherin, down N-cadherin and NF-KBprevention of EMT occurrence, and thus indirectly play a role in its anti-tumor recurrence and metastasis.
3. Feiliuping sirupu can inhibit tumor growth, reduce the side effects of chemotherapy, and improve the quality of life.
4. These effects in integrated treatment group (Feiliuping sirupu+CTX) have a stronger role in the trend.
5. The cases of colorectal cancer is broadly in line with the epidemiological trends. Yang deficiency of spleen and kidney is the most common type of dialectical of TCM.The Chinese treatment rate is100%.The COX regression analysis showed that the liver metastases is poor prognostic factors, and the integrated treatment is good prognostic factors for TTP.
6.Grouped according to treatment time, the past six years group has more TCM treatments and chemotherapy to achieve a better clinical benefit trend and higher quality of life improved rate、longer TTP, less hospital stay、costs、better cost-effectiveness ratio. But the first six year group has better stable disease rates, and the same OS.
7.Grouping according to the way of treatment, the integrated treatment group achieved better efficiency and clinical benefit rate, longer TTP and better cost-effectiveness ratio. At the same time simple Chinese medicine treatment group has a wealth of traditional Chinese medicine treatment, stable disease rates, fewer hospital days, and the same OS.
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