1、RT for hepatocelluar carcinomaQifeng WangDepartment of Radiation Oncology, Sichuan Cancer Hospital& Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China;Epidemiology (worldwide)Liver cancer incidence trend for selected regis

2、tries 1993-2002Center MM, et al. Cancer Epidemiol Biomarkers Prev 2011; 20(11): 23622368.Epidemiology (worldwide)Annual incidence rate by age group for selected registries 1998-2002Center MM, et al. Cancer Epidemiol Biomarkers Prev 2011; 20(11): 23622368.Epidemiology (China)Age-standardized rate of

3、liver cancerChen JG, et al. Chin J Prev Med 2010; 44(5): 383-389.Topics Liver function tests Staging systems Treatment guidelines Radiotherapy Toxicities Quality Of LifeLiver function testsLiver FunctionUptakeMetabolismConjugationExcretionimmunologyLiver function testsLiver function testsMechanismFa

4、ctorsPassive testsBilirubinIndirect information on the uptake, conjugation and excretion functionInfluenced by organic anion transporting polypeptide expression, and hemolysisAlbumin and coagulation factorsIndirect indicators of synthesis function-Dynamic quantitative testsIndocyanine green clearanc

5、e testIts exclusively cleared by hepaocytes, and excreted into the bile like bilirubin.Its dependent on hepatic blood flow, cellular uptake, and biliary excresion, just like intrhepatic shunting or thrombosis, steatosis, cholestatic patients. It reflects global liver function but not regional variat

6、ions.Galactose elimination capacity testThe metabolic capacity of the liverIts altered in environmental conditions or liver metabolism like liver regeneration and fasting.Hoekstra LT, et al. Ann Surg 2013; 257: 27-36.Conventional testsLiver function testsLiver function testsMechanismCharacteristics9

7、9mTc-Galactosyl serum albumin scintigraphy/SPECTIt binds to asialoglycoprotein receptors only on the hepatocyte cell membrane.It demonstrated a good relationship with conventional liver function tests and is not influenced by hyperbilirubinemia. It could distinguish between functional and nonfunctio

8、nal liver tissue and predict postoperative complication with high accuracy.99mTc-Mebrofenin hepatobiliary scintigraphy/SPECTSimilar to indocyanine green, it is taken up by hepaocyte via organic anion transporting polypeptide and undergoes biliary excretion without biotransformation.Cause of rapid bi

9、liary excretion, it is used for dynamic assessment of liver function. It measure functional remnant liver accurately. However, the uptake of mebrofenin can be affected by hyperbilirubinemia and hypoalbuminemia.Hoekstra LT, et al. Ann Surg 2013; 257: 27-36.Molecular testsTopics Liver function tests S

10、taging systems Treatment guidelines Radiotherapy Toxicities Quality Of LifeTNM stageNo liver function status, not perfect!Primary tumor (T)TxPrimary tumor cannot be assessedT0No evidence of primary tumorT1Solitary tumor without vascular invasionT2Solitary tumor with vascular invasion or multiple tum

11、ors none more than 5 cmT3aMultiple tumors more than 5 cmT3bSingle tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic veinT4Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneumRegional lymph nod

12、es (N)NxRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisDistant metastasis (M)M0No distant metastasisM1Distant metastasisAnatomic stage/prognostic groupsStage IT1N0M0Stage IIT2N0M0Stage IIIAT3aN0M0Stage IIIBT3bN0M0Stage IIICT4N0M0Stage IVAAny

13、 TN1M0Stage IVBAny TAny NM17th AJCC TNM stage, 2010.CLIP scoring systemVariableScoreChild-Pugh stageA0B1C2Tumor morphologyUninodular and extension 50%0Multinodular and extension 50%1Massive or extension 50%2AFP (ug/l)40004001Portal vein thrombosisNo0Yes1Perrone F, et al. Hepatology 1998; 28: 751-755

14、.BCLC staging classificationStageTumor statusPerformance StatusLiver functionVery early stage 0Single and 2 cm0Child-Pugh AEarly stageA1Single0No portal hypertension, normal bilirubinA2Single0Portal hypertension, normal bilirubinA3Single0Portal hypertension, abnormal bilirubinA43 tumors and 3 cm0Chi

15、ld-Pugh A-BIntermediate stageBMultiple/large0Child-Pugh A-BAdvanced stageCVascular invasion/extrahepatic spread1-2Child-Pugh A-BTerminal stageDAny3-4Child-Pugh CLlovet JM, et al. Semin liver dis 1999; 19(3): 329-338.BCLC treatment optionsEASL, AASLD, NCCN guidelines.Evidence-based guidelines in Japa

16、nMakuuchi M, et al. Hepatol Res 2008; 38(1): 37-51.BCLC treatment outcomes5y OS (%)Hepatic recurrence (%)CommentTransplant70-758Milan criteriaResection45-6068Solitary HCC without vascular invasion and portal hypertensionRFA505-20 (local recurrence) 3cm away from large vessels and dome of the liverTA

17、CE10cm and thrombosisSorafenib0100Only approved for Child-Pugh A and less benefit in thrombosis and extrahepatic metastasesOutcome 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) unsuitabl

18、e/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 LifeRadiotherapy Palliative therapy Local therapy (3DCRT, SBRT and charg

19、ed particle therapy) Tumor thrombosis therapy Combination with TACE and sorafenib Bridge to liver transplant Image and imaging guided RT Response assessmentPalliative therapySiteAuthorNo.RT regimenCR (%)PR (%)OSToxicitiesRecommendation doseLNZeng6250 (40-60) Gy/2 Gy23 (37.1)37 (59.7)9.4mGrade 3, 6 (

20、9.7%)50 Gy/2 GyLNYamashita2846-60 Gy/2 Gy5 (17.9)18 (64.3)13mMild50 Gy/2 GyBoneHe20550 (32-66) Gy/2 Gy61 (29.8)143 (69.7)7.4mMild50 Gy/2 GyLungJiang1350 (47-60) Gy/2 GySymptom 12/13RR 10 (76.9)70.7% (2y)Mild60 Gy/2 GyAdrenal glandZeng2250 (36-54) Gy/2 Gy11/14 (78.6)2/14 (14.3)10mMild50 Gy/2 GyRT for

21、 metastases in HCCZeng 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.Pall

22、iative 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)Conformal RTAn IMRT plan to deliver 65 Gy in 20 fractionsFeng M, et al. Semin Radiat Oncol 2011; 21: 271-277.Conformal RTReported studies of 3DCRT for local HCCAuthorNo.Eligibi

23、lityPVT (%)Child-B (%)RT regimenMargin (GTV-CTV-PTV)RR (%)Failure (%)OSToxicitiesDawson200027Phase I/II Unresectable-61.5 (28.5-90) Gy/1.5 Gy BidCTV: 1.0cmPTV: 0.5cm (0.3-3.0cm CC)5/11 (45)-11mRILD 1GI bleeding 3Seong200027Failed after TACE5 (18.5)10 (37.0)51.8 (39.6-60) Gy/1.8 Gy QDPTV: 2-3cmCR: 1/

24、24 (4.2)PR: 15/24 (62.5)DIH: 10 (37.0)EH: 4 (14.8)14m1y 55.9%2y 35.7%No grade 3 /4Liu200444Failed or unsuitable for TACE14 (31.8)12 (27.3)50.4 (39.6-60) Gy/2 Gy QDCTV: 1.0cmPTV: 0.5cm (0.5-2.5cm CC)CR: 6 (13.6)PR: 21 (47.7)DIH: 19 (43.2)EH: 6 (13.6)15.2m1y 60.5%2y 40.3%No grade 3 /4Ben-Josef200535Ph

25、ase II Unresectable-60.75 (40-90) Gy/1.5 Gy BidCTV: 1.0cmPTV: 0.5cm (0.3-3.0cm CC)-LR: 11/25 (44)DIH: 18/28 (64)EH: 12/23 (52) 15.2mRILD 5GI bleeding 9Liang2005128Inoperable34 (26.6)20 (15.6)40-60 Gy/4-8 Gy QIDPTV: 0.5-1.5CR: 8 (7)PR: 59 (49)IH: 62 (48)EH: 24 (19)20m1y 65%2y 43%RILD 19Mornex200627Ph

26、ase IISmall, cirrhosis011 (40.7)66 Gy/2 Gy QDCTV: 1.0cmPTV: 1-2cmCR: 20/25 (80)PR: 3/25 (12)LR: 6 (22)DIH: 11 (41)-Grade 4: 2 (Child-B)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

27、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 RTDose-response relationship in

28、 local RT for HCCPark 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 Hi

29、gh 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)SBRTAn SBRT plan to deliver 50 Gy in 5 fractionsFeng M, et al. Semin Radiat Oncol 2011; 21: 271-277.SBRTReported studies of SBRT for local HCCAuthorNo.PVT (%)Child-B (%)Tumor sizeRT regi

30、menOSRR (%)LC (%)Failure (%)ToxicitiesBujold2013Phase I/II10256 (54.9)07.2 cm(1.4-23.1)36 Gy (24-54)/6f7.0m55% (1y)CR: 11PR: 4387 (1y)IH: 72 (70.6)EH: 33 (32.4)Child progression 29%Kang2012Phase II475 (10.6)6 (12.8)2.9 cm(1.3-7.8)57 Gy (42-60)/3f68.7% (2y)CR: 38.3PR: 38.394.6 (2y)LR: 2 (4.3)DIH: 22

31、(46.8)EH: 10 (21.3)3 (6.4%) grade 3 GI toxicities2 (4.3%) grade 4 stomach perfusionChild progression 6 (12.8%)Price2012Phase I/II263 (12)12 (46) 6cm42 Gy (24-48)/3-5f77% (1y)60% (2y)CR: 15PR: 58NANANABae2012Retrospective2002 (10) 5cm50 Gy/10f100% (1y)87.9% (2y)CR: 35PR: 3585 (2y)LR: 3 (15)DIH: 14 (7

32、0)EH: 10 (50)Child progression 2 (10%)Huang2012Retrospective36NA7 (19)4.4 cm(1.1-12.3)37 Gy (25-48)/4-5f64% (2y)CR: 22PR: 36.687.6 (1y)75.1 (2y)EH: 20 (55.6)RILD 2 (5.5%)1 (2.8%) grade 3 ulcerAndolino2011Prospective60NA24 (40)3.2 cm(1-6.5)Child A: 34 Gy (30-48)/3fChild B: 40 Gy (24-48)/5f67% (2y)CR:

33、 30PR: 4090 (2y)LR: 3/17 (18)DIH: 12/17 (71)EH: 7/17 (42)22 (36.7%) grade 3 or more toxicitiesChild progression 12 (20%)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. Ca

34、ncer 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

35、 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 therapyProton (Bragg peak and modulated Bragg peak) and 18-MV photon depth do

36、se curvesSkinner HD, et al. Semin Radiat Oncol 2011; 21: 278-286.Charged particle therapyComparison between IMRT (photons) and protons for an unresectable HCCSkinner HD, et al. Semin Radiat Oncol 2011; 21: 278-286.Charged particle therapyDIH: intrahepatic metastasis out of field. EH: extrahepatic me

37、tastasis. 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.

38、 Int J Radiat Oncol Biol Phys 2010; 76: 460-6. Imada H, et al. Int J Radiat Oncol Biol Phys 2010; 96: 231-5.AuthorNo.ParticleMultiple sites (%)PVT (%)Child (%)Tumor sizeRT GyE/fOS (%)LC (%)Failure (%)Grade 3 ToxicitiesCommentBush2011Phase II76Proton11 (14)4 (5)B: 36 (47)C: 18 (24)5.5 cm37 (49%) 5 cm

39、63/1518.4mNALR: 15 (20)DIH: 23 (36)EH: 13 (17)0Komatsu2011242Proton29 (12)73 (30)B: 55 (23)C: 3 (1)82 (28%) 5 cm52-84/4-381y 905y 385y 90LR: 8 (3)8 (3%)Retrospective101Carbon20 (20)19 (18)B: 20 (20)C: 3 (3)27 (25%) 5 cm52.8-76/4-201y 875y 36.35y 93LR: 5 (5)4 (4%)Mizumoto2011Retrospective266Proton142

40、 (53)NAB: 60 (23)C: 3 (1)3.4 cm (0.6-13)62 (23%) 5 cm66/1072.6/2277/351y 875y 481y 985y 87NA8 (3%)Nakayama2011Prospective47ProtonNA7 (15)B: 9 (19)C: 3 (6)NA72.6/2277/351y 70.43y 501y 92.33y 88.1LR: 2 (4)DIH: 21 (45)EH: 8 (17)1 (2%)2cm to GIKawashima2011Retrospective60Proton9 (15)42 (70)B: 13 (22)C:

41、04.5 cm (2-10)18 (30%) 5cm76/2065/2660/103y 565y 253y 905y 86NA0Sugahara2010Prosepctive22Proton4 (18)11 (50)B: 11 (50)C: 011 cm (10-14)47.3-89/10-351y 642y 362y 87LR: 2 (9)DIH: 14 (64)EH: 6 (27)0 10cmImada2010Phase I/II64Carbon8 (13)45 (70)B: 15 (23)C: 04 cm (1.2-12)52.8/43y 56NALR: 4 (6)25 (39)hemo

42、tologilic50% stage III, 14% stage IVCharged 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 costTrans-arterial Radio-embolisation (TARE)Physical characteristics of TARE f

43、or HCCCompoundsHalf-lifeGamma raysBeta rays131I-labelled lipiodol8.04d364kevMax 0.6Mev, 2.3mm90Y-loaded microsphere16.9h155kevMax 2.1Mev, 2.6mm188Re-based compounds64.3hNoMax 0.937Mev, 2.5mmTAREIndication for TARE for HCCIndicationsEvidence-base levelUnresctable HCC (BCLC stage C)III2, III3, IVDown

44、staging therapyIII3, IVBridging therapyIII3, IVRecurrent HCCIII3, IVAdjuvant/neo-adjuvant therapyIII3, IVAndreana 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.TAREContraindications for TAREExaggerated hepatopulmonary shuntingRe

45、flux to the gastrointestinal tractAny contraindication for TACEAbsolute contraindicationsMain portal vein thrombosis/ occlusionSevere liver dysfunction or pulmonary in sufficiencyPregnancyLimited hepatic reserveRelative contraindicationsPartial or branch portal vein thrombosis/ occlusionPrior radiot

46、herapy involving the liverLau WY, et al. Int J Radiat Oncol Biol Phys 2011; 81(2): 460-467.TARE (summary)Treatment of HCC with the introduction of TAREAndreana L, et al. Cancer Treatment Review 2012; 38: 641-649. BrachytherapyCT guided brachytherapy for HCCCompared to EBRT: steeper isodose to the pe

47、riphery exposing less liver tissue spare more volume of liver not be influenced by movement comparatively inexpensiveRicke J, et al. Semin Radiat Oncol 2011; 21: 287-293.BrachytherapyProspective trial of CT guided brachytherapy for advanced HCCMohnike K, et al. Int J Radiat Oncol Biol Phys 2010; 78:

48、 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 m

49、ortality 4 (.9%) RILD 0BrachytherapyProspective trial of CT guided brachytherapy for advanced HCC: match-analysisMohnike K, et al. Int J Radiat Oncol Biol Phys 2010; 78: 172-179.Median OS (m)CLIP scoreBrachytherapy groupNon-brachytherapy groupP0-142.326.70.000222.85.00.003 318.33.80.007All37.518.10.

50、000Radiotherapy 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 assessmentTumor thrombosis therapy Extensive intrahepatic dissemination Decrease bl

51、ood supply to the normal liver Portal hypertension Lung thrombosis Deteriorating liver function Left untreated, OS: 2.4-4.0m Unclear optimal treatmentCharacteristics of tumor thrombosisTumor thrombosis therapyPortal vein tumor thrombosis (PVTT) and inferior vena cava tumor thrombosis (IVCTT)Hou ZJ,

52、et al. Int J Radiat Oncol Biol Phys 2012; 84(2): 362-368.Tumor thrombosis therapyProspective trial of TACE + BSC vs BSC in PVTTTreatmentNo.Size cmOSRRTACE+BSC8411.17.1m16/82 (19%)BSC8011.64.1m0P0.2110.001NALuo J, et al. Ann Surg Oncol 2011; 18: 413-420.Poor OS in HCC with thrombosisTumor thrombosis

53、therapyAuthorTTNo.TreatmentRT regimenOSRR (%)Xi, 2013RetrospectivePVTTIVCTT41SBRT+ Sorafenib (34.1%)36 Gy (30-48)/5-8 Gy13.0mCR: 15 (36.6), PR: 16 (39), SD: 7 (17.1)Rim, 2012RetrospectivePVTT453DCRT+TACE (88.9%)37.8-65.4 Gy/1.8-2.5 Gy13.9m, RR: 16.7mNonRR: 8mCR: 3 (6.7), PR: 25 (55.6), SD: 14 (31)Yo

54、on, 2012RetrospectivePVTT4123DCRT+TACE (70%)21-60 Gy/2-5 Gy10.6m, RR: 19.4mNonRR: 7mCR: 27 (6.6), PR: 133 (33), SD: 188 (46)Chuma, 2011PVTT20TAC+3DCRT30-48 Gy/7-16f12mCR: 1 (5), PR: 11 (55), SD: 8 (40)Match analysis20TAC-9.1mCR: 0, PR: 6 (30), SD: 7 (35)Koo, 2010IVCTT423DCRT+TACE45 Gy (28-50)/2.5-5

55、Gy11.7mCR: 6 (14.3), PR: 12 (28.6), SD: 12 (28.6)Retrospective29TACE-4.7mCR: 0, PR: 4 (13.8), SD: 7 (24.1)Huang, 2009RetrospectivePVTT3263DCRT/IMRT60 Gy/2-3 Gy4mCR: 19(5.8), PR: 40(12.2)Han, 2008ProspectivePVTT40CCRT+TACE45 Gy/1.8 Gy13.1m, RR: 19.9mNonRR: 11.4mCR: 0, PR: 18 (45), SD: 9 (22.5)Lin, 20

56、06PVTT22SBRT45 Gy/3 Gy6mCR:0, PR: 6 (27), SD: 2 (9)Prospective213DCRT45 Gy/1.8 Gy6.7mCR: 1 (5), PR: 4 (19), SD: 1 (5)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 2

57、011; 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 thrombosisTumor thrombosis therapyShirai S, et al. I

58、nt 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 PVTTIrradiate functional liver as little as possibleTumor thrombosis therapyAuthorNo.Size (cm)Child-PughRT regimenOSRR (%)Grade 3 ToxicitiesShirai267.1B: 13 (50%

59、)45-50 Gy/2.5 Gy10.3mCR: 00Prospective(4.4-12.3)C: 2 (7.7%)1y 44%PR: 8 (30.7)2y 30%SD: 16 (61.5)Shirai1911.0B: 3 (15.8%)45 Gy/2.5 Gy10.3mCR: 010 (52.7%)Prospective(8-20)C: 3 (15.8%)1y 47.4%PR: 7 (36.8)hematology2y 23.7%SD: 10 (52.7)Shirai S, et al. Int J Radiat Oncol Biol Phys 2009; 73: 824-831. Shi

60、rai S, et al. Int J Radiat Oncol Biol Phys 2010; 76: 1037-1044. SPECT-3DCRT for HCC with PVTTTumor thrombosis therapyInfluence 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%)Subgroup