原发性肝癌放射治疗

RT for hepatocelluar carcinoma,Qifeng WangDepartment of Radiation Oncology, Sichuan Cancer Hospital,Epidemiology (worldwide),Liver cancer incidence trend for selected registries 1993-2002,Center MM, et al. Cancer Epidemiol Biomarkers Prev 2011; 20(11): 23622368.,Epidemiology (worldwide),Annual incidence rate by age group for selected registries 1998-2002,Center MM, et al. Cancer Epidemiol Biomarkers Prev 2011; 20(11): 23622368.,Epidemiology (China),Age-standardized rate of liver cancer,Chen JG, et al. Chin J Prev Med 2010; 44(5): 383-389.,Topics,Liver function tests Staging systems Treatment guidelines Radiotherapy Toxicities Quality Of Life,Topics,Liver function tests Staging systems Treatment guidelines Radiotherapy Toxicities Quality Of Life,Liver function tests,Liver Function,UptakeMetabolismConjugationExcretionimmunology,Liver function tests,Hoekstra LT, et al. Ann Surg 2013; 257: 27-36.,Conventional tests,Liver function tests (clinical grading systems),Child-Pugh scoring system,Liver function tests,Hoekstra LT, et al. Ann Surg 2013; 257: 27-36.,Molecular tests,Topics,Liver function tests Staging systems Treatment guidelines Radiotherapy Toxicities Quality Of Life,TNM stage,No liver function status, not perfect!,7th AJCC TNM stage, 2010.,Staging systems,Most common used staging systems,CLIP scoring system,Perrone F, et al. Hepatology 1998; 28: 751-755.,BCLC staging classification,Llovet JM, et al. Semin liver dis 1999; 19(3): 329-338.,Topics,Staging systems Liver function tests Treatment guidelines Radiotherapy Toxicities Quality Of Life,BCLC treatment options,EASL, AASLD, NCCN guidelines.,Evidence-based guidelines in Japan,Makuuchi M, et al. Hepatol Res 2008; 38(1): 37-51.,BCLC treatment outcomes,Outcome estimate for HCC (Child-Pugh A),Dawson LA. Semin radiat oncol 2011; 21: 242-246.,BCLC treatment options,unsuitable for resection, transplant or RFA (early stage) unsuitable/refractory to TACE (intermediate stage) portal invasion (advanced stage) symptomatic alleviation (end stage),Radiotherapy role?,Topics,Staging systems Liver function tests Treatment guidelines Radiotherapy Toxicities Quality Of Life,Radiotherapy,Palliative therapy Local therapy (3DCRT, SBRT and charged particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessment,Radiotherapy,Palliative therapy Local therapy (3DCRT, SBRT and charged particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessment,Palliative therapy,RT for metastases in HCC,Zeng ZC, et al. Int J Radiat Oncol Biol Phys 2005; 63(4): 1067-1076. Yamashita H, et al. J Gastroenterol Hepatol 2007; 22(4): 523-527. He J, et al. Cancer 2009; 115: 2710-2720. Jiang W, et al. Clin exp metastasis 2012; 29(3): 197-205. Zeng ZC, et al. Jpn JCO 2005; 35(2): 61-67.,Palliative therapy (summary),RR: 76.9- 99.5% OS: 7.4- 13m RT regimen: 50-60 Gy/2 Gy Optimal dose (short-course?) RCT (RT vs BSC),Radiotherapy,Palliative therapy Local therapy (3DCRT, SBRT and charged particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessment,Conformal RT,An IMRT plan to deliver 65 Gy in 20 fractions,Feng M, et al. Semin Radiat Oncol 2011; 21: 271-277.,Conformal RT,Reported studies of 3DCRT for local HCC,Dawson LA, et al. JCO 2000; 18: 2210-8. Seong J, et al. Int J Radiat Oncol Biol Phys 2000; 47(5): 1331-5. Liu MT, et al. Jpn JCO 2004; 34(9): 532-9. Ben-Josef E, et al. JCO 2005; 23: 8739-47. Liang SX, et al. Cancer 2005; 103: 2181-8. Mornex F, et al. Int J Radiat Oncol Biol Phys 2006; 66(4): 1152-8.,DIH: intrahepatic metastasis out of field. EH: extrahepatic metastasis. LR: local recurrence. IH: intrahepatic metastasis.,Conformal RT,Dose-response relationship in local RT for HCC,Park HC, et al. Int J Radiat Oncol Biol Phys 2002; 54(1): 150-4.,Conformal RT (summary),Early stage unsuitable for S, transplant or RFA Focal intermediate stage unsuitable or refractory to TACE RR: 45-66.7%, OS: 11-20m, LR: 22-44%, DIH: 37-64% Recommended dose: 40-50 Gy/1.8-2.0 Gy High risk of toxicity in Child-Pugh B or C RCT (RT vs BSC in Child-Pugh B) RCT (RT + TACE/ RT alone in Child-Pugh A),SBRT,An SBRT plan to deliver 50 Gy in 5 fractions,Feng M, et al. Semin Radiat Oncol 2011; 21: 271-277.,SBRT,Reported studies of SBRT for local HCC,DIH: intrahepatic metastasis out of field. EH: extrahepatic metastasis. LR: local recurrence. IH: intrahepatic metastasis.,Bujold A, et al. JCO 2013; 31: 1631-9. Kang JK, et al. Cancer 2012; 7: 166-174. Price TR, et al. Cancer 2012; 118:3191-8. Bae SH, et al. Int J Radiat Oncol Biol Phys 2012; 82: e603-7. Huang WY, et al. Int J Radiat Oncol Biol Phys 2012; 84: 355-361. Andolino DL, et al. Int J Radiat Oncol Biol Phys 2011; 81: e447-53.,SBRT (summary),Considered for early stage unsuitable for S, transplant or RFA RR: 54-76.6%, 2yOS: 75.1-94.6%, LR: 4.3-18%, DIH: 46-71% Low risk of toxicity even in Child-Pugh B Trials (SBRT for Child-Pugh B) RCT (SBRT vs other standard treatments),Charged particle therapy,Proton (Bragg peak and modulated Bragg peak) and 18-MV photon depth dose curves,Skinner HD, et al. Semin Radiat Oncol 2011; 21: 278-286.,Charged particle therapy,Comparison between IMRT (photons) and protons for an unresectable HCC,Skinner HD, et al. Semin Radiat Oncol 2011; 21: 278-286.,Charged particle therapy,DIH: intrahepatic metastasis out of field. EH: extrahepatic metastasis. LR: local recurrence. IH: intrahepatic metastasis.,Bush DA, et al. Cancer 2011; 118: 3053-9. Komatsu S, et al. Cancer 2011; 117: 4890-4904. Mizumoto M, et al. Int J Radiat Oncol Biol Phys 2011; 81: 1039-45. Nakayama H, et al. Int J Radiat Oncol Biol Phys 2011; 80: 992-5. Sugahara S, et al. Int J Radiat Oncol Biol Phys 2010; 76: 460-6. Imada H, et al. Int J Radiat Oncol Biol Phys 2010; 96: 231-5.,Charged particle therapy (summary),Comparable outcome to S, better than other RT series 5yOS: 25-48%, 5yLC: 86-93%, DIH: 36-64% Largest benefit in Child-Pugh B or C and large tumor High cost,Trans-arterial Radio-embolisation (TARE),Physical characteristics of TARE for HCC,TARE,Indication for TARE for HCC,Andreana L, et al. Cancer Treatment Review 2012; 38: 641-649. Lau WY, et al. Int J Radiat Oncol Biol Phys 2011; 81(2): 460-467.,TARE,Contraindications for TARE,Lau WY, et al. Int J Radiat Oncol Biol Phys 2011; 81(2): 460-467.,TARE (summary),Treatment of HCC with the introduction of TARE,Andreana L, et al. Cancer Treatment Review 2012; 38: 641-649.,Brachytherapy,CT guided brachytherapy for HCC,Compared to EBRT: steeper isodose to the periphery exposing less liver tissue spare more volume of liver not be influenced by movement comparatively inexpensive,Ricke J, et al. Semin Radiat Oncol 2011; 21: 287-293.,Brachytherapy,Prospective trial of CT guided brachytherapy for advanced HCC,Mohnike K, et al. Int J Radiat Oncol Biol Phys 2010; 78: 172-179.,83 patients (140 lesions), pretreated 5.2 cm (1-15cm) 43 (52%) patients 2 lesions Child-A: 53 (64%), Child-B: 30 (36%), no PVTT Small tumors: 15-25 Gy prescribed dose Large tumors: 12and 15 Gy at 2-week interval TTP: 10.4m, LR: 5 lesions, OS: 19.4m Perioperative mortality 1 (1.2%) 30-day mortality 4 (.9%) RILD 0,Brachytherapy,Prospective trial of CT guided brachytherapy for advanced HCC: match-analysis,Mohnike K, et al. Int J Radiat Oncol Biol Phys 2010; 78: 172-179.,Radiotherapy,Palliative therapy Local therapy (3DCRT, SBRT and charged particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessment,Tumor thrombosis therapy,Extensive intrahepatic dissemination Decrease blood supply to the normal liver Portal hypertension Lung thrombosis Deteriorating liver function Left untreated, OS: 2.4-4.0m Unclear optimal treatment,Characteristics of tumor thrombosis,Tumor thrombosis therapy,Portal vein tumor thrombosis (PVTT) and inferior vena cava tumor thrombosis (IVCTT),Hou ZJ, et al. Int J Radiat Oncol Biol Phys 2012; 84(2): 362-368.,Tumor thrombosis therapy,Prospective trial of TACE + BSC vs BSC in PVTT,Luo J, et al. Ann Surg Oncol 2011; 18: 413-420.,Poor OS in HCC with thrombosis,Tumor thrombosis therapy,Xi M, et al. PLOS 2013; 8: e63864-70. Rim CH, et al. Jpn JCO 2012; 42: 721-9. Yoon SM, et al. Int J Radiat Oncol Biol Phys 2012; 82: 2004-11. Chuma M, et al. J Gastroenterol Hepatol 2011; 26: 1123-32. Koo JE, et al. Int J Radiat Oncol Biol Phys 2010; 78: 180-7. Huang YJ, et al. Int J Radiat Oncol Biol Phys 2009; 73: 1155-63. Han KH, et al. Cancer 2008; 113: 995-1003. Lin CS, et al. Jpn JCO 2006; 36: 212-7.,RT for HCC with tumor thrombosis,Tumor thrombosis therapy,Shirai S, et al. Int J Radiat Oncol Biol Phys 2009; 73: 824-831. Shirai S, et al. Int J Radiat Oncol Biol Phys 2010; 76: 1037-1044.,SPECT-3DCRT for HCC with PVTT,Irradiate functional liver as little as possible,Tumor thrombosis therapy,Shirai S, et al. Int J Radiat Oncol Biol Phys 2009; 73: 824-831. Shirai S, et al. Int J Radiat Oncol Biol Phys 2010; 76: 1037-1044.,SPECT-3DCRT for HCC with PVTT,Tumor thrombosis therapy,Influence of tumor thrombosis location on outcome,181 patients, Child-Pugh A or B 2D or 3D-CRT, 50 Gy (30-60)/2 Gy CR: 53 (29.3%), PR: 57 (31.5%) SD: 61 (33.7%), PD: 10 (5.5%),Hou ZJ, et al. Int J Radiat Oncol Biol Phys 2012; 84(2): 362-368.,Tumor thrombosis therapy (summary),Best outcome in preserved liver function, less extensive tumor thrombosis, responder to RT RR: 18-75.6%, OS: 4- 13.9m Response assessment is needed. Role of SBRT and SPECT,Radiotherapy,Palliative therapy Local therapy (3DCRT, SBRT and charged particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessment,Combined modality treatment,Cons of RT alone in locally advanced HCC,high risk of intrahepatic or extrahepatic metastases impossible to deliver tumoricidal dose high risk of RILD high risk of toxicity to adjacent GI organs,Combined modality treatment,Radiosensitizers in HCC,Systemic antiferritin (iodine-131 antiferritin antibody) Systemic conventional cytotoxic agents (adriamycin, 5FU, Xeloda, ) Regional pyrimidine analogs (BrdU, FdUrd, 5FU) Transcatheter Arterial Chemoembolization (TACE) Molecular-targeted agents (sorafenib, sunitinib, ),Chemotherapy and RT,Studies of RT with chemotherapy for advanced HCC,HAI: hepatic arterial infusion fluorodeoxyuridine.,Kim JY, et al. Radiat Oncol 2013; 8: 15-23. Chang HJ, et al. Int J Radiat Oncol Biol Phys 2012; 82: 817-25.Jang JW, et al. Int J Radiat Oncol Biol Phys 2009; 74: 412-8. McIntosh A, et al. Cancer 2009; 115: 5117-25. Han KH, et al. Cancer 113; 995-1003.,TACE and RT,TACE with RT in unresectable HCC,Xu LT, et al. EJSO 2011; 37: 245-251. Oh D, et al. Am JCO 2010; 33: 370-5. Zhou ZH, et al. BJR 2007; 80: 194-201. Li BS, et al. Am JCO 2003; 26: E92-9.,TACE and RT,TACE + RT vs TACE alone : Meta-analysis,Meng MB, et al. Radiotherapy and Oncology 2009; 92: 184-194.,Characteristics of included RCT,TACE and RT,TACE + RT vs TACE alone : Meta-analysis,Meng MB, et al. Radiotherapy and Oncology 2009; 92: 184-194.,Characteristics of included non-RCT,TACE and RT,TACE + RT vs TACE alone : Meta-analysis,Meng MB, et al. Radiotherapy and Oncology 2009; 92: 184-194.,Characteristics of included non-RCT,TACE and RT,TACE + RT vs TACE alone : Meta-analysis,Meng MB, et al. Radiotherapy and Oncology 2009; 92: 184-194.,RR ,1-5y OS ,TACE and RT,TACE + RT vs TACE alone : Meta-analysis,Meng MB, et al. Radiotherapy and Oncology 2009; 92: 184-194.,Poor trial quality,TACE and RT,Dose-response relationship in RT in local HCC TACE+RT? TACE for multiple lesions in advanced HCC Effect of number of lesions on RT?,TACE and RT,RT and TACE in locally advanced HCCDose-escalation study,Ren ZG, et al. Int J Radiat Oncol Biol Phys 2011; 79: 496-502.,Eligibility: Solitary lesion without metastases Unresectable or inoperable KPS 70 Child-Pugh A Normal function of other organs Tolerance of ABC Dose-constraint for OAR in 3DCRT/IMRT,Dose constraint: Liver: mean dose to normal liver limited to 23 Gy, V5 of 86%, V10 of 68%, V15 of 59%, V20 of 49%, V25 of 35%, V30 of 28%, V35 of 25%, and V40 of 20% Stomach and duodenum: D50 1ml,TACE and RT,RT and TACE in locally advanced HCCDose-escalation study,Dose escalation: Initial dose: 46 Gy for 10cm 40 Gy for 10cm Each cohort at increments of 4 Gy Up to 62 Gy for 10cm, 52 Gy for 10cm4 patients in each dose level, if DLT, 4 more patients, 2/8, terminated,Dose limiting toxicity: Grade 3 acute hepatic or gastrointestinal toxicity or any grade 5 treatment-related adverse event during irradiation or RILD,Ren ZG, et al. Int J Radiat Oncol Biol Phys 2011; 79: 496-502.,TACE and RT,RT and TACE in locally advanced HCCDose-escalation study,Included 40 patients, dose: 62 Gy for 10cm, no DLT; 52 Gy for 10cm, 1 RILD,Ren ZG, et al. Int J Radiat Oncol Biol Phys 2011; 79: 496-502.,TACE and RT,Role of RT in multiple HCC,Koon WS, et al. Int J Radiat Oncol Biol Phys 2010; 77: 1433-40.,TACE and RT,Role of RT in multiple HCC,Koon WS, et al. Int J Radiat Oncol Biol Phys 2010; 77: 1433-40.,IH: intrahepatic metastases, EH: extrahepatic metastases.,TACE and RT (summary),TACE+RT improve outcome than TACE alone RR: 41.9-87.8% vs 27.1-65.0%, 3y OS: 15-44.6% vs 5-24.0% high quality RCT needed high dose under the OAR constraints multiple lesions benefit only within RT field,Molecular-targeted agents and RT,Sorafenib in advanced HCC,Llovet JM, et al. NEJM 2008; 359: 378-390.,7.9 m vs 10.7m,2.8 m vs 5.5 m,Molecular-targeted agents and RT,Sorafenib potentiates irradiation effect: in vitro,Yu W, et al. Cancer Letters 2013; 329: 109-117.,Irradiation-induced proliferation DNA repair Irradiation-induced apoptosis Anti-angiogenesis,Molecular-targeted agents and RT,Sorafenib potentiates irradiation effect: in vivo,Yu W, et al. Cancer Letters 2013; 329: 109-117.,R: irradiation, 30S or 100S: 7 days of daily sorafenib at 30 mg/kg/d or 100 mg/kg/d p.o.,Molecular-targeted agents and RT,Sequential Sorafenib and RT better than Concurrent (in vitro),Wild AT, et al. PLOS one 2013; 8(6): e65726-38.,Surviving fraction,Apoptosis cells proportion,Molecular-targeted agents and RT,Sequential Sorafenib and RT better than Concurrent (in vivo),Wild AT, et al. PLOS one 2013; 8(6): e65726-38.,Tumor growth delay,Molecular-targeted agents and RT,RT and Targeted agents for advanced HCC,Cha J, et al. Int J Radiat Oncol Biol Phys 2010; 78: s306. Chi KH, et al. Int J Radiat Oncol Biol Phys 2010; 78: 188-193.,Molecular-targeted agents and RT,Active clinical trial registered on ClinicalTrials. gov,Combined modality treatment (summary),Sequential RT and sorafenib, a promising combination More studies warranted of RT and targeted agents HCC specific novel agents needed,Radiotherapy,Palliative therapy Local therapy (3DCRT, SBRT and charged particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessment,Bridge to liver transplant,Goals of bridge treatment,Control tumor growth and vascular invasion and therefore decrease the dropout from waiting list Improve the post-transplant outcome by reducing the risk of postoperative recurrence Downstage to make patients eligible for transplantation,Bridge to liver transplant,Published studies of RT as a bridge to transplant for HCC,Sandroussi G, et al. Transplant International 2010; 23: 299-306. Katz AW, et al. Int J Radiat Oncol Biol Phys 2012; 83(3): 895-900.,3DCRT and SBRT are safe and effective bridge therapy for HCC patients awaiting liver transplant.,Radiotherapy,Palliative therapy Local therapy (3DCRT, SBRT and charged particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessment,Imaging in HCC,Imaging of RT in HCC,Brock KK. Semin radiat oncol 2011; 21(4): 247-255.,Imaging in HCC,Simulation of RT in HCC,Brock KK. Semin radiat oncol 2011; 21(4): 247-255.,Multi-phase CT Oral contrast,Imaging in HCC,Target identification of RT in HCC,Voroney JP, et al. Int J Radiat Oncol Biol Phys 2006; 66: 78-791.,CT and MR are complement.,Imaging in HCC,CTV margin of RT in HCC (shanghai),Wang MH, et al. Int J Radiat Oncol Biol Phys 2010; 76(2): 467-476.,Inclusion criteria (149 patients): radical resection at least 1 cm of a normal liver margin no satellite nodules no treatment for the primary lesions,Microscopic extension (ME) distribution,Imaging in HCC,CTV margin of RT in HCC (shanghai),Wang MH, et al. Int J Radiat Oncol Biol Phys 2010; 76(2): 467-476.,Score system for ME,Cumulative distribution of ME with different score,Recommended: CTV = GTV + 4mm,Imaging in HCC,CTV margin of RT in HCC (Beijing),Wang WH, et al. Radiat Oncol 2010; 5: 73-79.,Inclusion criteria (76 patients): radical resection at least 1 cm of a normal liver margin no satellite nodules no treatment for the primary lesions,ME positive rate and distance by grade and AFP,Whole-mount slides,Imaging in HCC,CTV margin of RT in HCC (Beijing),Wang WH, et al. Radiat Oncol 2010; 5: 73-79.,Correlation between grade and ME distance,Recommended: grade 1: 0.2mm grade 2: 4.5mm grade 3: 8.0mm,Cumulative distribution of ME by grade,Imaging in HCC,Motion management of RT in HCC,Brock KK. Semin radiat oncol 2011; 21(4): 247-255.,ABC,4D treatment,Abdominal compression,Imagi