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1、Normal Tissue Toxicity in Thoracic Irradiation,Zhongxing Liao, MD The University of Texas M. D. Anderson Cancer Center,The 5th Shanghai International Conference on Radiation Oncology, Shanghai, China November 18-21, 2006,COMBINED MODALITY THERAPY,Concurrent chemo-radiation improves both local-region
2、al tumor control and survival of NSCLC patients but at the expense of increased toxicity,Outcome of 265 NSCLC treated with concurrent Chemoradiation,2-year OS 41% 5-year OS 19%,Wang et al., IJROBP, 2006,The Onset Time for Maximal Esophagitis Score,Wei, Xiong, IJROBP, 2006,Grade 1-4: 93.0%, Grade = 3
3、: 20.5%,Chemo-Radiotherapy - Improvement Strategies:,Technology improvements (IMRT, IGRT, Proton) More effective chemotherapeutic agents or conjugates (or radioenhancers) Multimodality therapy Chemotherapy + Radiotherapy + Molecular Targeting Chemotherapy + Radiotherapy + Immunotherapy Chemotherapy
4、+ Radiotherapy + Protectors,Thoracic irradiation Esophageal cancer NSCLC SCLC Mesothelioma Major dose limiting toxicities: Pulmonary toxicities Esophageal toxicities Cardiac toxicities,Thoracic Radiation Therapy,Treatment Related Toxicity,Grade depends on scoring system (SWOG, RTOG, CTC) Patient fac
5、tors: smoking, intrinsic sensitivity to intervention, co-morbidity, lung function Tumor factors: GTV, location Treatment factors: Chemotherapy: agents, schedule, intensity Radiation: dose, volume, fractionation, modality,TRP and scoring systems SWOG/CTC,TRP and scoring systems-RTOG,Hernado et al. in
6、t J Radiat Oncol biol phys 2001, 51:650-659,Clinical Factors and Symptomatic TRP,Courtesy of Dr. Thomas Guerrero, MD, PhD,Intrinsic sensitivity,Courtesy of Dr. Thomas Guerrero, MD, PhD,Patients: higher incidence of RP for lower lobe tumors YES Graham 1995, Yorke 2002 Seppenwoolde 2004, Bradley 2005
7、NO Yu 2003,Lung regions, tumor location,Response of mouse/rat lung to partial volume base = more sensitive than apex Liao 1995, Travis and Tucker 1997 Kahn 1998, 2002, Moiseenko 2000 Vujaskovic, in press,Tumor location and heart dose,Marks et al. Mean heart dose higher for lower lobe tumors No assoc
8、iation between mean heart dose and RT-associated dyspnea BUT: no higher incidence of TRP for lower lobe tumors in this dataset (Yu 2003) Heart dose may still be important,Lung function loss and heart dose in rats after proton irradiation,Peter Van Luijk Cancer Research 2005; 65 (15): 6509 - 6511,Con
9、current Chemotherapy and TRP,Type of chemotherapy Intensity of chemotherapy Different combinations of chemotherapy,Concurrent chemotherapy,CRT alone Seppenwoolde et al. 2003,ConChT and CRT Liao 2005 Taxanes Cisplatin/carboplatin Etoposide,Concurrent chemotherapy,Seppenwoolde et al . 2003, in regard
10、to Tsujino et al. 2003,Cisplatin/carboplatin plus taxane,RP grade 2,Freedom from grade 2 TRP as a function of time,Wang et al., in press,Freedom from grade 2 TRP as a function of time,Wang et al., in press,Dose-volume parameters,Point estimates in DVH space: Volume above threshold dose: V13, V20, V3
11、0 V5 Minimum dose to “hottest” % volume: D15, D25, D45 Overall parameters (whole DVH) Mean lung dose (MLD) Effective volume (Veff),MLD and TRP,Correlation of lung mean dose and V5 postoperative pneumonia/ARDS,Wang et al., IJROBP, 2005,V5 and TRP,Wang et al., IJROBP, 2006,Correlation of Dosimetric fa
12、ctors,Wang et al., IJROBP, 2006,Dose volume parameters are highly correlated,Seppenwoolde et al. 2003, Liao, 2005,Reducing Toxicity,Radiation technology 3D CRT vs IMRT Photon vs proton Understanding the biology of Toxicity Cytokine Cytoprotection Molecular target of TRT and development of targeted t
13、herapy,3D IMRT,Intensity Modulated Radiation for Lung Cancer,IMRT Reduced TRP for NSCLC treated with concurrent chemoradiation,IMRT Reduced TRP for NSCLC treated with concurrent chemoradiation,DVH of patients with grade 3 TRP,DVH consideration in thoracic Radiotherapy,Dose constraint for lung V20 35
14、% Mean Lung dose 20Gy V5 = 65%,Low Dose RT and Lung toxicity,Randomized Trial of 3DCRT vs IMRT,Primary Objectives,To Compare the time to developing CTC 3.0 grade 3 TRP in Arm 1 and Arm 2,Statistical considerations,We assume the percentage of = grade 3 radiation pneumonitis-free rate by year is estim
15、ated according to the following table We assume an annual 2% or 3-year 6% loss-to-follow up, to get 80% power, we need 75 patients per group or a total of 150 evaluable patients. Adaptive randomization will be used to have 40%:60% accrual in a period of 2 to 3 years with additional 1 year of f/u. To
16、tal study duration = 3 to 4 years. Average enrollment with 2-yr accrual: average: 6.3 patients / month. Average enrollment with 3-yr accrual: average: 4.2 patients / month,Reducing Toxicity,Radiation technology 3D CRT vs IMRT Photon vs proton Understanding the biology of Toxicity Cytokine Cytoprotection Molecular target of TRT and development of targeted therapy,Photon Proton Comparison,Depth dose curve for unmodulated and modulated 160 Mev proton b
