1、肿瘤代谢调节疗法（cancer metabolic modulation therapy,CMMT）石汉平 FACS中山大学附属第一医院卫计委医学参考报-营养学频道卫计委肿瘤代谢与营养杂志中国肿瘤营养与支持治疗专业委员会定义与背景Knox LS,et al.Ann Surg.1983;197(2):152-62.Lieffers JR,et al.Am J Clin Nutr.2009;89(4):1173-9.葡萄糖葡萄糖丙酮酸乳酸乳酸Cori 循环胞浆线粒体丙酮酸乙酰辅酶AATP三羧酸循环丙酮酸脱氢酶 50%50%脂肪脂肪癌从口人肿瘤代谢调节疗法（cancer metabolic modu
2、lation therapy,CMMT）是作者提出的一种全新的肿瘤治疗方法，顾名思义它是采用不同手段调节肿瘤患者正常细胞代谢、干扰肿瘤细胞代谢，从而达到预防和治疗肿瘤的目的。它包含营养疗法，但是内容更加丰富，肿瘤营养疗法是通过营养素实施抗肿瘤治疗，而代谢调节疗法则是通过各种手段调节代谢实施抗肿瘤治疗，这些手段包括（1）营养素调节，（2）能量调节，（3）营养途径调节，（4）药物调节，（5）手术调节，（6）运动调节，（7）心理调节，（8）生物反馈调节。CMMT是另外一种疗法，是一套组合拳，其地位和作用与手术、放疗、化疗等肿瘤传统治疗方法相似，但是代谢调节疗法对机体的损伤更小，毒副反应更少，患者依从
3、性更好。适应证一个始动因素恶性肿瘤两个相互作用肿瘤对宿主宿主对肿瘤三个中心环节摄食减少（厌食）体重丢失肌肉减少四个调控机制神经内分泌激素肿瘤代谢因子炎症细胞因子自由基五个临床后果能量负债生活质量下降体力活动能力下降社会心理影响生存时间缩短CMMT目的并非仅仅提供能量及营养素、治疗营养不良，其更加重要的目标在于代谢调节、控制肿瘤。由于所有荷瘤患者均需要代谢调节治疗，所以，其适应证为：1）荷瘤肿瘤患者，2）营养不良的患者。营养素调节Foster R,et al.PLoS One.2012;7(9):e45061.1.减少葡萄糖供给Miao YR,et al.Clin Cancer Res.2013
4、;19(8):2107-16.细胞活性肿瘤重量细胞数量无病生存时间Tayek JA,et.al.,Metabolism.1997;46:140 145静脉注入葡萄糖后胰岛素分泌反应，(A)正常体重，(B)低体重，癌症患者胰岛素分泌显著低于正常对照组(P .05)2.维持血糖稳定 Proposed role of miR-451 in the regulation of LKB1 signaling in response to fluctuating glucose.Two different growth schemes of tumor spheroids(gray filled circ
5、le)with same initial size in response to fluctuating and steady glucose(green solid line).Kim Y,et al.miR451 and AMPK mutual antagonism in glioma cell migration and proliferation:a mathematical model.PLoS One.2011;6(12):e28293TPP脱羧酶丙酮酸脱氢酶复合物 3.促进葡萄糖氧化thiamine(open circle)DCA(closed circle)Hanberry B
6、S,Berger R,Zastre JA.High-dose vitamin B1 reduces proliferation in cancer cell lines analogous to dichloroacetate.Cancer Chemother Pharmacol.2014;73(3):585-94Abdelwahab MG,et al.The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma.PLoS One.2012;7(5):
7、e36197 4.提高脂肪比例治疗前经过2个月治疗后Zuccoli G,et al.Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet:Case Report.Nutr Metab.2010,22(7):33Vanek VW,et al.Nutr Clin Pract.2012;27(2):150-92.Th0细胞向Th1、Th2两个方向分化，Th1淋巴细胞具备促炎作用，Th2细胞相反。-3FA对Th1细胞有特异性细胞毒作
8、用，间接增强了Th2细胞的抗炎效能5.选择合适脂肪Chandi Charan Mandal CC,et al.Fish oil prevents breast cancer cell metastasis to bone.Biochem Biophys Res Commun.2010;402(4):602607Javier A.Menendez JA,et al.Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil.A new family of ger
9、osuppressant agents.Cell Cycle.2013;12(4):555578.secoiridoid polyphenols，裂环烯醚萜多酚(橄榄苦苷)，具有抗衰老及外来毒物兴奋效应，从而具有预防肿瘤的作用。维生素E：、4种形式，抗氧化活性最高，其他3种相对生物活性分别为0.5、0.25、0.01TestDiet 50588%CHO15%CHOa10%CHOaCHO55.28.015.610.6Protein23.269.458.263.5Fat21.622.626.225.9NOTE:Values are given in%kcala CHO content is 70%
10、high amylose cornstarchTable Macronutrient breakdown of diets usedHo VW,etal.A low carbohydrate,high protein diet slows tumor growth and prevents cancer Initiation.Cancer Res.2011.71(13):4484-93 6.提高蛋白质供给The 15%CHO diet reduces the incidence of tumors in a spontaneous mouse model of breast cancer.血糖
11、胰岛素体重肿瘤发生率生存时间最新版（2009年）ESPEN指南：肿瘤病人的氨基酸需要量推荐范围最少为1g/kg/d到目标需要量的1.2-2g/kg/d之间。Bozzetti F等认为，肿瘤恶病质病人蛋白质的总摄入量（静脉+口服）应该达到1.8-2 g/kg/d，BCAA应该达到0.6 g/kg/d，EAA应该增加到1.2 g/kg/d。严重营养不良肿瘤病人的短期冲击营养治疗阶段，蛋白质给予量应该达到2 g/kg/d；轻中度营养不良肿瘤病人的长期营养补充治疗阶段，蛋白质给予量应该达到1.5g/kg/d（1.25-1.7 g/kg/d）。日常饮食不足时，应该口服营养补充，口服营养补充仍然不足时，应
12、该由静脉补充。Bozzetti F,Bozzetti V.Is the intravenous supplementation of amino acid to cancer patients adequate?A critical appraisal of literature.Clin Nutr.2013;32(1):142-6.预消化水解蛋白配方,同时含有游离氨基酸和短肽，可充分利用人体双通道氮源吸收。且短肽和游离氨基酸在吸收过程中都不受胃，肠蛋白酶的影响。Zaloga GP.Physiologic effects of peptide-based enteral formulas.Nu
13、tr Clin Pract.1990;5(6):231-7.7.选择合适蛋白质编号分组动物数量处理肿瘤形成率123456假处理组肿瘤组肿瘤+WPWP肿瘤+WPHWPH101111101010盐水注射AOM+DSSAOM+DSS+WPWPAOM+DSS+WPHWPH091.9%91.9%033.3%0WP，whey protein，乳清蛋白；WPH，whey protein hydrolyzate，乳清蛋白水解物AOM，azoxymethane，氧化偶氮甲烷；DSS，dextran sodium sulfate，硫酸葡聚糖钠结论：与乳清蛋白相比，乳清蛋白水解物具有更强的肿瘤预防与抑制作用Atta
14、allah W,et al.Whey protein versus whey protein hydrolyzate for the protection of azoxymethane and dextran sodium sulfate induced colonic tumors in rats.Pathol Oncol Res.2012;18(4):817-22.能量调节Colman RJ,et al.Science.2009;325(5937):201-4.8.限制能量摄入Colman RJ,et al.Science.2009;325(5937):201-4.Colman RJ,e
15、t al.Science.2009;325(5937):201-4.Saleh AD,et al.Caloric restriction augments radiation efficacy in breast cancer.Cell Cycle.2013;12(12):1955-63.肿瘤体积肿瘤体积营养途径调节Median survival ratesPN=12.5(10-15)months No PN=9.0(8-10)months Shang E,et al.JPEN.2006;30(3):222-30.SPN在围手术期、放化疗、终末期肿瘤、营养不良患者的营养支持中意义特别重要。9.
16、部分肠外营养 Shang E,et al.JPEN.2006;30(3):222-30.生活质量随观察时间的变化*表示两组间有统计学上的显著差异（P 0.05）营养干预的五阶梯模式能量70%蛋白质100%药物调节10.抑制乳酸代谢 Sutendra G,Michelakis ED.Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology.Front Oncol.2013;3:38.Mei ZB,et al.Survival benefits of metformin for colorectal cancer
17、 patients with diabetes:a systematic review and meta-analysis.PLoS One.2014 Mar 19;9(3):e91818.11.抑制糖异生二甲双胍 MetforminNoto H,et al.Latest insights into the risk of cancer in diabetes.J Diabetes Investig.2013;4(3):225232.Horita N,Miyazawa N,Kojima R,Inoue M,Ishigatsubo Y,Ueda A,Kaneko T.Statins reduce
18、 all-cause mortality in chronic obstructive pulmonary disease:a systematic review and meta-analysis of observational studies.Respir Res.2014;15:80.12.改善脂肪代谢BACKGROUND:There is conflicting evidence for the role of statins in the primary prevention of colorectal cancer(CRC).We conducted a case control
19、 study(N=357,702)in the non-elderly adult US population(age=18-64 years)with the primary objective to examine the association between CRC and statin use.PATIENTS AND METHODS:MarketScan databases were used to identify patients with CRC.A case was defined as having an incident diagnosis of CRC.Up to t
20、en individually matched controls(age,sex,region and date of diagnosis)were selected per case.Statin exposure was assessed by prescription tracking in the 12 months prior to the index date.Conditional logistic regression was used to adjust for multiple potential confounders and calculate adjusted odd
21、s ratios(AOR).RESULTS:The mean age of participants was 54 years;52%males and 48%females.In a multivariable model,any statin use was associated with 26%reduced odds of CRC(AOR,0.74,95%confidence interval(CI),0.72-0.77,p0.001).Age-stratified analyses showed a stronger effect of statins on CRC in parti
22、cipants aged 55 years or younger(AOR,0.67,95%CI,0.63-0.71,p0.001)than in participants aged above 55 years(AOR,0.79,95%CI,0.76-0.82,p0.001);the age-by-statin interaction was statistically significant(p0.001).The dose-response analyses performed with simvastatin only showed a trend towards significanc
23、e between the duration of simvastatin exposure and odds of developing CRC(p=0.06).CONCLUSIONS:Statins appears to reduce the risk of CRC in non-elderly US population.Chemoprevention with statin might be more effective in non-elderly US populationSehdev A,Shih YC,Huo D,Vekhter B,Lyttle C,Polite B.The
24、Role of Statins for Primary Prevention in Non-elderly Colorectal Cancer Patients.Anticancer Res.2014 Sep;34(9):5043-50.外科调节2014年ASCO关于肥胖与癌症的指南中指出，减重手术是治疗肥胖的重要手段。该指南又指出，因为减重手术预防癌症发生的实验均在未患癌症的肥胖患者中进行，因此并没有对照组进行研究，所以减重手术并没有直接证据来证明其预防癌症的作用，但是考虑到肥胖与许多癌症的发生有关，ASCO还是将减重手术作为预防癌症的重要手段。对于手术时机的选择，ASCO认为BMI30kg
25、/m2合并2型糖尿病、高血压、高血脂等代谢紊乱的患者，均应积极进行减重手术，同时减少能量摄入、增加运动以及必要的咨询和药物治疗。13.体重管理与减重Muzumdar R,et al.Visceral adipose tissue modulates mammalian longevity.Aging Cell.2008;7(3):438-40.Survival curve of the three groups of rats(AL-fed,dashed line;VF-removed,dotted line;and CR,solid line).能量限制自由摄食内脏脂肪切除14.切除内脏脂肪
26、Huffman DM,et al.Cancer Prev Res(Phila).2013;6(3):177-87.肿瘤病灶数量肿瘤生存时间整体雌性雄性运动调节Fong DY,et al.BMJ.2012;344:e70.15.身体活动Gould DW,Lahart I,Carmichael AR,Koutedakis Y,Metsios GS.Cancer cachexia prevention via physical exercise:molecular mechanisms.J Cachexia Sarcopenia Muscle.2013;4(2):111-24.生物反馈Fig.2 R
27、esults:change in exercise capacity(mean change in 6MWD from pre to post intervention)measured by the 6 min walk distance(6MWD)in reviewed observational trials.Granger CL,McDonald CF,Berney S,Chao C,Denehy L.Exercise intervention to improve exercise capacity and health related quality of life for pat
28、ients with Non-small cell lung cancer:a systematic review.Lung Cancer.2011;72(2):139-5316.身心放松Quist M,Rrth M,Langer S,Jones LW,Laursen JH,Pappot H,Christensen KB,Adamsen L.Safety and feasibility of a combined exercise intervention for inoperable lung cancer patients undergoing chemotherapy:a pilot s
29、tudy.Lung Cancer.2012;75(2):203-8.Variable(n=23)Base mean(SD)Post mean(SD)Change(95%CI)p valueBMI25.1(5.0)25.3(4.8)0.2(0.3 to 0.5)0.076Lung capacity FEV11.76(0.70)1.96(0.63)0.20(0.01 to 0.41)0.061Aerobic capacity VO2peak(L/min)1.48(0.41)1.57(0,41)0.09(0.02 to 0.16)0.014Functional capacity 6 MWD(m)52
30、4.7(88.5)564.0(88.6)39.3(12.5 to 66.1)0.006Muscle strength Leg press(kg)70.4(26.9)86.9(28.8)16.5(11.5 to 21.7)0.000 Chest press(kg)30.8(13.2)40.3(16.3)9.5(6.4 to 12.7)0.000 Lat machine(kg)35.8(13.8)39.2(17.6)3.4(0.0 to 6.7)0.049 Abdominal crunch(kg)24.9(10.7)29.5(11.3)4.6(3.2 to 6.0)0.000 Lower back
31、(kg)35.3(14.1)43.1(16.2)7.8(4.8 to 10.8)0.000 Leg extension(kg)38.6(15.5)45.1(18.9)6.5(4.1 to 8.9)0.000疗程与疗效时机与疗程实施CMMT越早越好，考虑到CMMT的临床效果出现较慢，建议以4周为一个疗程。疗效评价1 近期指标（实验室参数）血常规，电解质，肝功能、肾功能、炎症参数（IL-1、IL-6、TNF、CRP）、血乳酸、营养套餐（白蛋白、前白蛋白、转铁蛋白、视黄醇结合蛋白、游离脂肪酸）等，每周检测1-2次。2 中期指标 人体测量参数、人体成分分析、生活质量评估、体能评估、肿瘤病灶评估（双径法）、PET-CT代谢活性。每4-12周评估一次。3 远期指标 生存时间，每年评估一次。荷瘤患者的代谢调节疗法内容非常丰富，涉及营养素调节、能量调节、药物调节、手术调节、运动调节多个方面。日常生活中简便易行，切实有效的措施为：限制能量摄入，减少葡萄糖供给，提高蛋白质供给，加强运动。实验医学向临床应用转化。小 结热烈欢迎2015中国国际肿瘤营养论坛第三届全国肿瘤营养与支持治疗学术会议第一届海峡两岸肿瘤营养高峰论坛2015年5月8-10日 北京谢谢光临敬请批评指正
