放射性消化道(系统)副反应(损伤)临床研究

1、放射性消化道(系统)副反应(损伤)临床研究放射性消化道(系统)副反应(损伤)临床研究一、放射性损伤临床（应用）研究的现状。物理技术、生物学基础与临床特征二、消化道放射性毒副作用的临床研究一、放射性损伤临床（应用）研究的现状。物理技术、生物学基础与研究放射治疗所致正常组织、器官副反应所涉及的相关内容DoseLETFractionationTimeDose-ratePathogenesisVolumeCombined TxReTx ToleranceModifiersJoiner M, van der Kogel A. (eds). Basic Clinical Radiobiology (4th

2、).2009, Hodder Arnold:London研究放射治疗所致正常组织、器官副反应所涉及的相关内容DosNat Rev Clin Oncol, 2013,10:52-Time of discoveryKilovoltage era 1900-1940Megavoltage era 1946-1996Computer-assisted 1996-2012The futureCurative, conservative, and cost-effective treatment. 物理技术Nat Rev Clin Oncol, 2013,10:52Lancet Oncol, 2012;1

3、3: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 in new equipment, QA, and training. evolve and be modified over time.2. extended follow-up is needed to

4、 measure outcomes, especially, such as reduction of long term toxic effects or second malignant diseases. 3. commercial sponsorship is more difficult than for new drugs. 4. ethical issues arise in testing a theoretically superior.5. patients management could change in other ways.Lancet Oncol, 1. new

5、 RT techni(1). The WHO Handbook for Reporting Results of Cancer Treatment (1979)(2). Common Terminology Criteria for Adverse Events (CTCAE) by NCI (1988)(3). Acute & Late Radiation Morbidity Scoring System by EORTC/RTOG (1983-1992)(4). LENT SOMA Scales by EORTC/RTOG (1995) Late effect of normal tiss

6、ues: four categories of Subjective, Objective, Management and Analytic parameters Int J Radiat Oncol Biol Phys, 1995;31(5)临床特征(1). The WHO Handbook for RepoASTRO, AAPM, Red J. Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC). the Red J, 2010;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

7、量化的剂量效应与剂量体积关系。(2) 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。(3) 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。The Challenges1. 放疗前基础临床特征2. 放射性毒副反应的准确分类、分期, endpoint measurements, show a large degree of interpatient variability in incidence and severity3. 长期的随访与资料保存ASTRO, AAPM, Red J. QuantitatiA System for Continual Qualit

8、y Improvement of Normal Tissue Delineation for Radiation Therapy Treatment PlanningBreunig J, the Red J, 2012;83:703-A System for Continual Quality生物学基础及其临床应用Barnett GC, et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer, 2009;9:134. Kerns SL

9、, et al. Radiogenomics : using genetics to identify cancer patients at risk for development of adverse effects following radiotherapy. Cancer Discov, 2014;4:155.生物学基础及其临床应用Barnett GC, et al. 候选基因病例对照关联研究筛选出易感基因Single-nucleotide polymorphism (SNP,单核苷酸多态性) 位点的。The goals of the radiogenomics: (i) to de

10、velop an assay capable of predicting which patients are most likely to (ii) to obtain information to assist with the elucidation of the molecular pathways responsible for候选基因病例对照关联研究筛选出易感基因Single-nu放射基因组学：全基因组关联分析 (genome-wide association studies, GWAS) 发现临床放射敏感性的预测基因放射基因组学：全基因组关联分析 (genome-wide ava

11、n Oorschot R, et al. Reduced activity of double-strand break repair genes in prostate cancer patients with late normal tissue radiation toxicity. the Red J, 2014;88:664. 500 prostate cancer patients, 34 over-responding VS 27 non-responding of grade 3 toxicity to the bladder and/or rectum at more tha

12、n 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, RAD51) may potentially be used to assess the risk for late radiation toxicity.

13、Foro P, etal. Relationship between radiation-induced apoptosis of T lymphocytes and chronic toxicity in patients with prostate cancer treated by radiation therapy: A Prospective Study. the Red J, 2014;88:1057. 214 patients were prospectively included. Peripheral blood before treatment and irradiated

14、 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 before radiation therapy was ass

15、ociated with the probability of developing chronic GU toxicity.van Oorschot R, et al. Reduced早晚反应组织、早晚期毒副反应临床观测终点（指标）的选择严重程度的分级发生率的高低时间：发生的早晚、持续的长短其他治疗的影响LENT SOMA、CTCAENO!口腔、咽部（上消化呼吸道）黏膜早晚反应组织、早晚期毒副反应LENT SOMA、CTCARTOG acute radiation morbidity scoring criteria01234No change over baselineInjection

16、/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, et al. the

17、 Red J, 1995;31(5):1341-46RTOG acute radiation morbidity定义食管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；在计划CT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20%；食管周长由于受吞咽活动的影响在CT图像上有明显差异，因此，传统的DVHs可能并不能准确反映部分的剂量体积；三维剂量学参数的使用（例如：剂量-表面积、剂量-周长直方图，解剖校正DVHs）作为预测值的作用并不是很清楚。推荐使用CTCAE 定义食管体积面临的问题整个食管的长度上至环状软骨，下至胃食管胃与小肠1. 急、慢性毒性包括

18、恶心、腹泻、梗阻、出血溃疡、体重下降、穿孔等。2. 受照射剂量与体积，单组肠袢 V15 = 120 cc ，所有肠袢 V45 = 195 cc 。目前没有关于胃的数据。慢性毒性与急性有关，而且要注意最大剂量。3. 手术、化疗有明显的关系。4. 推荐使用CTCAE胃与小肠1. 急、慢性毒性包括恶心、腹泻、梗阻、出血溃疡、十二指肠Verma J, et al. Red J, 2014;88:357Limiting V55 to below 15 cm3 may reduce the risk of duodenal complications.Duodenal toxicity was asses

19、sed on the basis of endoscopic findings (endoscopy was performed in patients with symptoms of gastrointestinal toxic effects such as pain or bleeding)它不适合于胰腺癌放疗？十二指肠Verma J, et al. Red J, 201肠道 Small bowel & large bowel loops were contoured 2 cm above the target volume. CTCAE 3.0 with median follow-

20、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 toxicity to less than 5%. Chopra S, et al. Predictors of Grade 3 or Higher Late Bowel Toxicity in Patients Undergoing Pelvic Radiat

21、ion for Cervical Cancer: Results From a Prospective Study. the Red J, 2014;88:630肠道 Small bowel & large bowel 直肠Lyman-Kutcher-Burman 模型：n = 0.09 (0.040.14);m = 0.13 (0.100.17)；而TD50 = 76.9 (73.780.1) Gy。前列腺癌放疗提供了相关的资料。a significant reduction of bowel dysfunctional symptoms was confirmed in men selec

22、ted for IGRT, even though they had larger volumes of rectum treated to higher doses. Red J, 2013;85:1018-直肠Lyman-Kutcher-Burman 模型：a siOptimising Radiotherapy Bowel Injury Therapy (ORBIT) in UKBowel Disease Questionnaire-Bowel subset score (IBDQ-B) & Changes in quality-of-life secondary endpoints in 6 & 12 monthsLENT-SOMAAndreyev HJN, et al. Lancet 2013; 382: 2084-给病人有计划的处置方案就可以明显改善病人胃肠道状态。Optimising Radiotherapy Bowel Ferreira MR, et al. Lancet Oncol 2014; 15: e139-1. Similarities between radiation-induced gastrointestinal toxicity and inflammatory b