Stereotactic Body Radiotherapy (SBRT) For HCC T A R E K S H O U M A N P R O F. R A D I A T I O N O N C O L O G Y N C I, C A I R O U N I V.

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1 Stereotactic Body Radiotherapy (SBRT) For HCC T A R E K S H O U M A N P R O F. R A D I A T I O N O N C O L O G Y N C I, C A I R O U N I V.

2 Hepatocellular carcinoma (HCC), is a major health problem worldwide. It is the 6 th most common cancer and the 3 rd most common cause of cancer death in the world. It is the 1 st cancer in males in Egypt. Eighty-five percent of cases occur in developing countries, largely in Asia and Africa, while in the United States, it is the fastest growing cancer

3 The Barcelona Clinic Liver Cancer Group staging system for HCC. M, metastasis classification; N, node classification; PS, performance status; RFA, radiofrequency ablation; PEI: percutaneous ethanol injection; TACE, transarterial chemoembolization

4 Limitations of Radiotherapy to liver tumors Tolerance of whole liver < 28Gy with conventional fractionation Movement of liver with respiration Nearby sensitive structures: Duodenum, stomach, esophagus Heart S. cord, kidney

5 Radiation Induced Liver Disease Classic RILD occurs most often within 2 months following radiation therapy Treatment for RILD is symptomatic and it may progress to liver failure, despite maximal supportive care.

6 History of radiotherapy to liver The technical development of 3D conformal radiotherapy initiated in the 1980s renewed interest in the treatment of primary and metastatic liver tumors. Numerous advances in external-beam radiation therapy allow for more accurate targeting, and make aggressive dose-fractionation strategies possible using techniques such as SBRT originally developed for the treatment of intracranial malignancies (i.e., radiosurgery) SBRT has since been adopted for the treatment of extracranial diseases. The use of SBRT for liver malignancies was pioneered by Dr. Blomgren et al at the Karolinska Institute, Stockholm in the early 1990s. Classic RILD is uncommon in modern radiation therapy series, when the dose to the liver can be kept below recommended level.

7 Stereotactic Body Radiation Therapy SBRT An external beam radiation therapy method used to very precisely deliver a high dose of radiation to an extracranial target within the body, using either a single dose or a small number of fractions ASTRO definition (Potters et al, IJROBP 2010)

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9 Advances in HCC Radiation addressing challanges Accurate target identification Triphasic CT MRI, PET Gold fidaucial markers Accounting for organ movement 4D-CT Breath holding Abdominal compression Respiratory gating Sophisticated treatment delivery 3D CRT IMRT VMAT CYBERKNIFE

10 Treatment Planning Imaging Triphasic CT (best seen in arterial phase) The three CT phases should be acquired under breath hold (preferably end-expiratory) MRI GTV PET-CT may be fused with CT to improve image of

11 Reproducibility of SBRT system CRANIOCAUDAL MARKER MOTION: 8MM ANTERIORPOSTERIOR MARKER MOTION: 4-6MM LATERAL MARKER MOTION: 4MM

12 Organ motion Tumour motion must be accounted for to ensure proper delivery of the radiation to the tumour and to avoid unnecessary dose to the surrounding healthy tissue

13 Motion Management techniques

14 Organ motion

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17 Day 2 Anterior (Gantry 0) Lateral (Gantry 270)

18 Critical structures and constraints Priority Dose Limits Organ 6# 3# EQD 2Gy Volume Liver Hard* 19 Gy 15 Gy >700 cc spared Liver (minus CTV) Hard* 18 Gy 13 Gy Dmean Kidney Hard <12 Gy 10 Gy 12 Dmean Spinal Cord Hard 27 Gy 20 Gy mm Cord PRV Dmax Spinal Cord Hard 24 Gy 18 Gy 36 Dmax Duodenum Hard 36 Gy 27 Gy ml Small Bowel Hard 36 Gy 27 Gy ml Stomach Hard 36 Gy 27 Gy ml Oesophagus Hard 36 Gy 27 Gy ml Large Bowel Hard 36 Gy 27 Gy ml 2. Ribs Objective 54 Gy 39 Gy ml 2. Heart Objective 39 Gy 30 Gy 74 1mL 2: Skin Objective 39 Gy 30 Gy 74 1mL

19 SBRT TECHNIQUE Breathing motion control via breath hold or abdominal compression Generally frameless setup Target delineation: GTV based on CT +/or MRI fused to planning scan CTV = GTV PTV = GTV+ 5-7mm radial, 10-15mm sup-inf Arcs or multiple non-coplanar beams Prescription 70-90% isodose line Image guidance with EPID/CONE BEAM with each fraction

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23 Computed tomography sections demonstrating typical locations treated with stereotactic body radiation therapy. Areas indicated with hatched lines can be safely treated with SBRT, although these areas are difficult to approach for percutaneous ablation. Liver tumors located adjacent to the stomach and bowels (dotted areas) are not suitable for SBRT. Other unmarked areas can be treated either with SBRT or percutaneous ablation.

24 TREATMENT RESULTS R E V I E W O F L I T E R A T U R E

25 Objectives

26 INDICATIONS stage A-B, child A-B

27 INDICATIONS 3 lesions Diameter of largest lesion 60 mm (or feasible by planning; at least 700 cm³ of uninvolved liver) Adequate liver function Life expectancy > 3-6 months

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29 Results of SBRT for liver mets

30 Author/ Design Patients Child-Pugh Vascu-lar Dose frac-tionation Median CR%, PR% Survival-Median publication/ inv-olv. scheme follow-up (m) year (m) *Choi 34 Retrospective 15 A 4 PVT 18pat:10x5Gy B 2pat: 5x10Gy 60 Méndez Phase I-II 6 A x Gy 12.9 NRP 22.1 Romero 32 Retrospective 2 B 2 PTV 2006 **Kwon Retrospective 38 A 0 3x10-13Gy NRP 4 B (daily) 26 Louis 36 Retrospective 22 A 4 PVT 3x15Gy NRP B (10-12 days) 29 #Seo 27 Retrospective 34 A NRP 33-57Gy() B & 40-44() 61 Iwata 37 Phase II 5 A NRP 50-55Gy in 10 fr 14.5 NRP NRP ? B Goyal 38 Retrospective 17 NRP NRP 24-45Gy in Mean 0% NRP HCC 1-3 fractions 10 83% 3 IHC, 8Metas (HCC) (HCC) Cardenes Phase I 6 A 3 PVT A: 3x12-16Gy NRP 6 B=7 B: 3x12-14Gy 56 5 B 8 later 5x8Gy Andolino Retrospective 36 A NRP A:3x12-16 Gy whole Gr. 24 B B: 5x8Gy 40 NT: 20.4, Bujold (23bridge T) Phase I-II 102 A 56 (TVT) 6 x 4-9 Gy T: (at 4.5 y 78%) 17

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36 Hepatocellular carcinoma case that could not be effectively or safely treated with any treatment except for stereotactic body radiation therapy. The tumor invading the vena cava is enhanced in arterial phase and shows a defect in portal phase on dynamic computed tomography (A and B). An axial view of radiation dose distribution. The isodose lines (white lines) from inner to outer represent 40, 30, 20, and 10 Gy, respectively (C).

37 TRANSARTERIAL CHEMOEMBOLIZATION (TACE) Results Author/ Publication/ Year Design Patients* Child-Pugh Chemotherapy CR%, RR% Survival- (12/24m) (%) Pelletrier Rand. TACE vs cons 21 NA Doxo 33% 24%/NA GETCH Rand. TACE vs cons 50 A: 100 Cis 16% 62%/38% Pelletrier Rand. TACE tam vs TAM 37 A:76 B:24 Cis +tamoxifen - 24% 51%/24% Llovet Rand TACE vs TAE vs cons 40 A:69 B:31 Doxo 35% 82%/63% Lo Rand. TACE vs cons 40 NA Cis 27% 57%/31%

38 PHASE III I M P O R T A N T O N G O I N G T R I A L S

39 RADIATION THERAPY ONCOLOGY GROUP RTOG 1112 RANDOMIZED PHASE III STUDY OF SORAFENIB VERSUS STEREOTACTIC BODY RADIATION THERAPY FOLLOWED BY SORAFENIB IN HEPATOCELLULAR CARCINOMA Schema

40 INCLUSION CRITERIA STRATIFY IAEA PROTOCOL (NCI, CAIRO) HCC (biopsy or radiological ). Age Number of lesions: not more than 3 lesions Lesion size: up to 10 cm for a single lesion (and up to 10 cm cumulative diameter Child-Pugh A or B BCLC Stage A/B Must be fit for SBRT and TACE Unsuitable/unwilling for resection or transplant or radiofrequency ablation (RFA) Distance between GTV (lesion) and luminal structures (including esophagus, stomach, duodenum, small or large bowel) is >10 mm CENTER SOLITARY LESION VS MULTIPLE SIZE 5CM OR MORE Arm I TACE Arm II SBRT Gy/3F Or 42-54Gy/6F

41 Conclusion The integration of new technologies has raised an interest in radiotherapy for hepatocellular carcinoma, with literature evolving to support its efficacy. Active investigation of SBRT has recently started, yielding promising local control rates. However, information on optimal treatment indications, doses, and methods remains limited We are waiting for the results of randomized trials as RTOG and IAEA ones to clarify important points as sorafenib and TACE in addition to SBRT

42 THANK YOU