放射性消化道(系统)副反应(损伤)临床研究.ppt

1、放射性消化道(系统)副反应(损伤)临床研究研究放射治疗所致研究放射治疗所致正常组织、器官正常组织、器官副反应所涉及的相关内容副反应所涉及的相关内容 LET Fractionation Time Dose-rate Pathogenesis ReTx Tolerance ModifiersJoiner M,van der Kogel A.(eds).Basic Clinical Radiobiology(4th).2009,Hodder Arnold:LondonNat Rev Clin Oncol,2013,10:52-Time of discoveryKilovoltage era 1900

2、-1940Megavoltage era 1946-1996The futureCurative,conservative,and cost-effective treatment.Lancet Oncol,2012;13:e1691.new RT techniques and technologies.2.evidence shows their dosimetric advantages.under the assumption that BUTFor new drugs,randomised trials 1.substantial investments have to be made

3、 in new equipment,QA,and training.evolve and be modified over time.to measure outcomes,especially,such as reduction of long term toxic effects or second malignant mercial sponsorship is more difficult than for new drugs.4.ethical issues arise in testing a theoretically superior.5.patients management

4、 could change in other ways.(1).The WHO Handbook for Reporting Results of Cancer Treatment(1979)(2).Common Terminology Criteria for Adverse Events(CTCAE)by NCI(1988)(3).&Radiation Morbidity Scoring System by EORTC/RTOG(1983-1992)(4).by EORTC/RTOG(1995)Late effect of normal tissues:four categories of

5、 ubjective,bjective,anagement and nalytic parameters 1995;31(5)ASTRO,AAPM,Red J.Quantitative Analysis of Normal Tissue Effects in the Clinic().the Red J,;76(3):S(1)通过现有资料的总结，对于正常组织特定观测终点，提供量化通过现有资料的总结，对于正常组织特定观测终点，提供量化的剂量效应与剂量体积关系。的剂量效应与剂量体积关系。(2)根据上述剂量体积的数据根据上述剂量体积的数据与模型，给临床提供合理的毒性分类与工作指南。与模型，给临床提供

6、合理的毒性分类与工作指南。(3)提出有助于提出有助于正确估测和减轻急性、晚期放射治疗副作用的研究方向。正确估测和减轻急性、晚期放射治疗副作用的研究方向。1.放疗前基础临床特征放疗前基础临床特征2.放射性毒副反应的准确分类、分期放射性毒副反应的准确分类、分期,endpoint measurements,show a large degree of interpatient variability in and 3.长期的随访与资料保存长期的随访与资料保存A System for Continual Quality Improvement of for Radiation Therapy Trea

7、tment PlanningBreunig J,the Red J,2012;83:703-Barnett GC,et al.Normal tissue reactions to radiotherapy:towards tailoring treatment dose by genotype.Nat Rev Cancer,2009;9:134.Kerns SL,et al.Radiogenomics:using genetics to identify cancer patients at risk for development of adverse effects following r

8、adiotherapy.Cancer Discov,2014;4:155.候选基因病例对照关联研究筛选出易感基因候选基因病例对照关联研究筛选出易感基因Single-nucleotide polymorphism(,单核苷酸多态性单核苷酸多态性)位点的。位点的。The goals of the:(i)to develop an assay capable of predicting which patients are most likely to (ii)to obtain information to assist with the elucidation of the molecular

9、pathways responsible for放射基因组学：全基因组关联分析放射基因组学：全基因组关联分析(genome-wide association studies,GWAS)发现临床放射发现临床放射敏感性的预测基因敏感性的预测基因van Oorschot R,et al.Reduced activity of in prostate cancer patients with late normal tissue radiation toxicity.the Red J,2014;88:664.500 prostate cancer patients,34 over-respondin

10、g VS 27 non-responding of grade 3 toxicity to the bladder and/or rectum at more than 1 time point beyond 2 years of follow-up.DNA damage repair kinetics(-H2AX assay)and expression profiles of DNA repair genes were determined in ex vivo irradiated lymphocytes.Induction levels of DSB repair genes(eg,R

11、AD51)may potentially be used to assess the risk for late radiation toxicity.Foro P,etal.Relationship between radiation-induced and chronic toxicity in patients with prostate cancer treated by radiation therapy:A Study.the Red J,2014;88:1057.214 patients were prospectively included.Peripheral blood b

12、efore treatment and irradiated with 8 Gy.The percentage of CD4 and CD8 T lymphocytes that underwent radiation-induced apoptosis was assessed by flow cytometry.198 cases with Late GI and GU toxicity and mortality were correlated.in vitro radiation-induced apoptosis of CD4 T lymphocytes assessed befor

13、e radiation therapy was associated with the probability of developing chronic GU toxicity.早晚早晚反应组织、反应组织、早晚早晚期毒副反应期毒副反应临床临床观测终点（指标）观测终点（指标）的选择的选择严重程度严重程度的分级的分级发生率发生率的高低的高低时间：时间：发生的早晚、持续的长短发生的早晚、持续的长短其他治疗其他治疗的影响的影响LENT SOMA、CTCAENO!RTOG acute radiation morbidity scoring criteria01234No change over bas

14、elineInjection/may experience mild pain not requiring analgesicPatchy mucositis that may produce an inflammatory serosanguinous discharge/may experience moderate pain requiring analgesia Confluent fibrinous mucositis/may include severe pain requiring narcotic Ulceration,hemorrhage or necrosisCox JD,

15、et al.the Red J,1995;31(5):1341-46定义定义体积面临的问题体积面临的问题 整个食管的长度上至环状软骨，下至胃食管连接部；整个食管的长度上至环状软骨，下至胃食管连接部；在计划在计划CT扫描时需包括一部分颈部和上腹部；扫描时需包括一部分颈部和上腹部；一些研究没有包括颈部食管，导致食管绝对体积小了一些研究没有包括颈部食管，导致食管绝对体积小了20%；食管周长由于受吞咽活动的影响在食管周长由于受吞咽活动的影响在CT图像上有明显差图像上有明显差异，因此，传统的异，因此，传统的DVHs可能并不能准确反映部分的剂可能并不能准确反映部分的剂量体积；量体积；三维剂量学参数的使用（

16、例如：剂量三维剂量学参数的使用（例如：剂量-表面积、剂量表面积、剂量-周周长直方图，解剖校正长直方图，解剖校正DVHs）作为预测值的作用并不是）作为预测值的作用并不是很清楚。很清楚。推荐使用推荐使用CTCAE 1.急、慢性毒性包括恶心、腹泻、梗阻、出血溃疡、急、慢性毒性包括恶心、腹泻、梗阻、出血溃疡、体重下降、穿孔等。体重下降、穿孔等。2.受照射剂量与体积，单组肠袢受照射剂量与体积，单组肠袢 V15=120 cc，所有肠，所有肠袢袢 V45=195 cc。目前没有关于目前没有关于的数据。的数据。慢性毒性与急性有关，慢性毒性与急性有关，而且要注意最大剂量。而且要注意最大剂量。3.手术、化疗有明显

17、手术、化疗有明显的关系。的关系。4.推荐使用推荐使用CTCAEVerma J,et al.Red J,2014;88:357Limiting V55 to below 15 cm3 may reduce the risk of duodenal complications.Duodenal toxicity was assessed on the basis of endoscopic findings(endoscopy was performed in patients with symptoms of gastrointestinal toxic effects such as pain

18、 or bleeding)它它不不适合于胰腺癌放疗适合于胰腺癌放疗？Small bowel&large bowel loops were contoured 2 cm above the target volume.CTCAE 3.0 with median follow-up of 18 months.V15 Gy SB and LB are independent predictors of late grade 3 or higher toxicity.Restricting V15 SB&LB to 275 cc&250 cc can reduce grade 3 or higher

19、toxicity to less than 5%.Chopra S,et al.Predictors of Grade 3 or Higher Late Bowel Toxicity in Patients Undergoing Pelvic Radiation for Cervical Cancer:Results From a Prospective Study.the Red J,2014;88:630Lyman-Kutcher-Burman 模型：模型：n=0.09(0.040.14);m=0.13(0.100.17)；而而TD50=76.9(73.780.1)Gy。前列腺癌放疗前列腺

20、癌放疗提供了相关的资料。提供了相关的资料。a significant reduction of bowel dysfunctional symptoms was confirmed in men selected for IGRT,even though they had larger volumes of rectum treated to higher doses.Red J,2013;85:1018-Optimising Radiotherapy Bowel Injury Therapy(ORBIT)in UKBowel Disease Questionnaire-Bowel subse

21、t score(IBDQ-B)&Changes in quality-of-life secondary endpoints in 6&12 monthsLENT-SOMAAndreyev HJN,et al.Lancet 2013;382:2084-给病人有计给病人有计划的处置方划的处置方案就可以明案就可以明显改善病人显改善病人胃肠道状态。胃肠道状态。Ferreira MR,et al.Lancet Oncol 2014;15:e139-1.Similarities between radiation-induced gastrointestinal toxicity and inflamm

22、atory bowel disease2.Inflammatory bowel disease:a blueprint for radiation-induced bowel toxicity?Radiation dose to the pancreas and risk of diabetes mellitus in cancer survivors:a retrospective cohort studyLancet Oncol,2012;13:1002-3468 survivors of a childhood cancer treated in France and the UK be

23、tween 1946 and 1985,2520 were returned.The risk increased strongly with dose to the tail of the pancreas,up to 20-29 Gy reached a plateau.The estimated RR at 1 Gy was 1.61.Compared with did not receive RT,the RR was 11.5 who received 10 Gy or more.The body-mass index,strong independent effect(p0.0001).And younger than 2 years at time of RT(p=0.02).谢谢 谢谢 聆聆 听，听，敬请批评指正！敬请批评指正！