Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

External Beam Radiotherapy for Hepatocellular carcinoma

1,559 views

Published on

Latest advances in external beam radiotherapy for hepatocellulalar carcinoma.

Presented at "Liver Disease awareness week" 2014 Singapore

Published in: Health & Medicine

External Beam Radiotherapy for Hepatocellular carcinoma

  1. 1. Latest advances in radiotherapy for hepatocellular carcinoma Liver disease awareness week Hepato-pancreato-biliary Association (Singapore) 27th Sept 2014 Dr Bala Vellayappan MBBS, GDFM, FRANZCR Associate Consultant Radiation Oncology National University Cancer Institute, Singapore
  2. 2. Outline • Radiotherapy basics • Challenges in treating HCC • State-of-the-art techniques in RT delivery • Role of RT in HCC – Evidence review • Toxicities and Dose-volume criteria in radiotherapy planning • Take home messages 2
  3. 3. What are the forms of radiotherapy? External beam radiotherapy • Photon beam 3D conformal Intensity Modulated (IMRT) Arc therapy (VMAT/Tomo) Stereotactic body radiotherapy (SBRT) • Particle beam Protons, charged particles Internal radiotherapy •Brachytherapy •Unsealed sources I-131, Sr-89, Y-90 3
  4. 4. Radiotherapy dictum • Dose response seen in tumours and normal organs • Maximize therapeutic window (maximum dose to tumour, minimum dose to normal organs) 4
  5. 5. Not too long ago… • Not much role for RT in liver cancers, save palliative treatment • Technical inability to get a curative dose to the tumour without damaging liver • HCC written off as a “radioresistant” disease • RT for liver tumours hardly featured in any radiation oncology text books • Radiation oncologists “switch off” when liver cancers were being discussed at HPB tumour boards 5
  6. 6. Radiotherapy is not what it used to be … 6
  7. 7. More recently… • Significant improvement in image guidance and conformal RT delivery • Better understanding of dose-volume relationship of liver tolerance • Emerging evidence of role of RT in primary and secondary liver tumours • More acceptance of ablative RT as a complementary therapy for HCC 7
  8. 8. Liver radiotherapy reports 8 Klein, Dawson IJROBP 2012
  9. 9. What are the challenges and opportunities for RT in HCC?
  10. 10. Uncertainty margins 11
  11. 11. Ways to address motion • Image guidance (IGRT) • Limit motion • Quantify actual motion • Track motion • Treat at certain phases of respiration 12
  12. 12. Image guidance then and now… Positional verification based on bony contours More accurate alignment using on-board cone beam CT 13
  13. 13. MRI-LINAC 14
  14. 14. Ways to address motion • Image guidance • Limit motion • Quantify actual motion • Track motion • Treat at certain phases of respiration 15
  15. 15. Custom vacuum bag • Customised immobilisation device to accommodate the patients entire body • Immobilisation device can be mounted onto the treatment couch • Vacuum Bag 16
  16. 16. Abdominal compressor • Useful for abdominal treatment and lower lobe lung tumours • Paddle board applied to upper abdomen to limit diaphragmatic motion 17
  17. 17. Ways to address motion • Image guidance • Limit motion • Quantify actual motion • Track motion • Treat at certain phases of respiration 18
  18. 18. 4D CT • Multiple series of CT taking through volume (fast acquisition) • Movement through various phases of respiration reconstructed to quantify actual motion of tumour – no more guessing! 19 https://www.youtube.com/watch?v=DfijRBvaG7o
  19. 19. Ways to address motion • Image guidance • Limit motion • Quantify actual motion • Track motion • Treat at certain phases of respiration 20
  20. 20. Real time tumour tracking (RTTT) • Elegant technique which allows the beam to “breathe” in tandem with the patient • Requires fiducial placement insitu, and external infra-red markers • Real time computer controlled adaptation 21 Valentine TCRT 2014
  21. 21. Ways to address motion • Image guidance • Limit motion • Quantify actual motion • Track motion • Treat at certain phases of respiration 22
  22. 22. Respiratory Gating • Radiation beam is turned on only in certain phases of respiration • Limits the amount of normal tissue being unnecessarily irradiated. 23 https://www.youtube.com/watch?v=lh5aH_vwOC0 Varian® Real-time Position Management™ (RPM) system
  23. 23. Active breathing co-ordinator 24 • Patient coached with audio-visual feedback • Freeze breathing for about 15-20 seconds, using a valve • Patient can release valve anytime • Radiation delivered only when valve is closed
  24. 24. Era of conformal RT techniques
  25. 25. Evolution of RT over the years 2D planning, based on bony landmarks Poor tumour localization Non conformal dose distributions 3D planning, based on CT images Better tumour localization More conformal dose distribution 4D planning, with incorporation of functional imaging Excellent tumour localization Highly conformal dose distributions, with adequate sparing of normal organs IMRT, Arc therapy 26 1950 - 1990 1990 – early 2000 Present
  26. 26. 3D conformal Radiotherapy • Based on 3D imaging (CT) • Forward planned • Multi-leaf collimators used to shape treatment field 27 JACMP 2013; 14(3)
  27. 27. IMRT / VMAT Intensity Modulated Radiotherapy Volumetric Modulated Arc Therapy • Inverse planning • Radiation oncologists volume out the areas of risk, and the areas to avoid • Dosimetrist imputes cost function into planning system • Computer generates treatment plan and field shapes 28
  28. 28. SBRT (Stereotactic Body Radiotherapy) • Very conformal dose distributions • Best suited for smaller tumours (<6cm) • Highly potent doses, high dose per fraction • Motion management integrated • Online image guidance (pre and post) • Few number of fractions ( 3 to 5) 29
  29. 29. Is there a biological edge in SBRT? • High dose per fraction (~8Gy threshold) • Postulated mechanisms 1. Ablative treatment 2. Endothelial damage 3. Immune - mediated – RT increases tumour antigen specific immune response 1. Abscopal effects – Local therapy causes systemic response (cytokine mediated) 30
  30. 30. SBRT – Linac based @ NCIS/NUH 31
  31. 31. Robotic radiosurgery • Cyberknife system (Accuray) • 6MV Linac mounted onto a robotic arm • Non-isocentric, non coplanar treatment (1400 angles) • Highly conformal doses, sharp dose fall off, better sparing of normal organs • Latest version includes RTTT 32
  32. 32. Proton therapy • Unique dosimetric advantages. Lower entrance and exit dose! • Collateral damage minimized • BUT, very expensive • Real estate requirement is huge • Evidence still emerging about it’s superiority 33
  33. 33. What is the role of RT in HCC?
  34. 34. Multimodal treatment is important Local therapy •Resection •Transplant •RFA •PEI •RT Loco-regional •TACE •SIRS (y-90) Systemic •Biologics •Chemo 35
  35. 35. 36
  36. 36. 37
  37. 37. RT has potential role across all stages of HCC 38 Klein IJROBP 2013
  38. 38. RT has potential role across all stages of HCC 39 Klein IJROBP 2013
  39. 39. Role of definitive RT in those not suited for surgery, RFA 40 Dawson, ASTRO
  40. 40. Michigan Retrospective :RFA vs. SBRT Liu, GI ASCO 2012 41 The reported toxicities •SBRT ~ 1%, mostly RILD •RFA ~ 4% (pneumothorax, hemothorax, sepsis, small bowel infarction, esophageal perforation)
  41. 41. RT has potential role across all stages of HCC 42 Klein IJROBP 2013
  42. 42. RT as a bridge to transplant Klein IJROBP 2013 Retrospective series from Sandroussi showed no local progression or morbidity at time of transplant. Explant necrosis 50 – 100% 43
  43. 43. Phase II study,Proton therapy • N= 76 • 63Gy/3 weeks, protons • Med PFS 36 months ( 95% 30 – 42m) • Med survival : CPA 34m, CPB 13m, CPC 12m • 18 patient had liver transplantation – 6 had path CR – 7 had microscopic residual disease 44 Bush, Cancer 2011
  44. 44. RT has potential role across all stages of HCC 45 Klein IJROBP 2013
  45. 45. RT in portal vein thrombosis • PVT is a poor prognostic factor. Precludes surgery and arterial-directed therapies • RT has been used with PVT – Sometimes in combination with TACE • Recanalization occurs in ~30 to 80% post RT • However, it is a slow process – Median time to maximal response 6 months – Median survival 4 to 13 months 46 Post RT Dawson, ASTRO 2013
  46. 46. RT trials for HCC with PVT 47 Klein, Dawson IJROBP 2013
  47. 47. Bujold JCO 2013 • N = 102 • PVT 55% • Median dose 36Gy/6# • 1 year LC 87%( 78-93%) • Dose response >30Gy • Survival worse with PVT – (11m vs 20.5m) 48
  48. 48. Changes in Liver function post RT 49 months Bujold, ASTRO 2011
  49. 49. RT has potential role across all stages of HCC 50 Klein IJROBP 2013
  50. 50. RT + TACE vs TACE • Observational studies suggest survival benefit post TACE • N= 73 ( 35 TACE repeated, 38 received RT) 2 year survival TACE + RT TACE alone All 37% 14% 5 – 7 cm 63% 42% 8 – 10 cm 50% 0 % Shim, Liver Int 2005 51
  51. 51. What about CP B and C patients? • Toxicity lowest and survival best in CP7 versus >B7 • Spare as much as liver as possible – >800cc should get less than 10 Gy (c.f 18Gy in CP A) • Comparative trials are needed in this area 52
  52. 52. PMH experience • N=39 ; ~70% CP B7, ~63% PVT • 30 to 45Gy/6# • MS ~10m, Median TTP ~19 m • Prognostic factors – CP >B7 ( 13.5 vs 18 m) – Bridge to transplant (7.9m vs 30.7m) Culleton, Green Journal 2014 53
  53. 53. If all else fails.. • RT has been used as an effective palliative modality for a long time Study N Dose / fractions Pts with pain improvement (%) Soliman JCO 2013 41 (21 HCC) 8 / 1 48 (at 1 month) Bydder JMIRO 2003 28 (all LM) 10 / 2 63 (at 6 weeks) Leibel IJROBP 1987 94 (all LM) 21 / 7 (whole liver) 74 Borgelt IJROBP 1981 109 (all LM) 30 / 15 25.6 / 16 20 / 10 21 / 7 55 (at 1 month) 54
  54. 54. • N=40 (21 with HCC) • 8Gy x 1 – short and sweet • CP A or B • At one month, 50% had decrease in pain • 25% had improvement in QoL 55
  55. 55. Potential RT toxicities Clinical •Radiation Induced Liver disease (RILD) 1. Classic : Anicteric hepatomegaly, ascites, elevated liver enzymes (ALP>AST/ALT) –2 weeks to 3 months 2. Non-classic : Elevation of transaminases, reactivation of Hep B, Liver function decline/ worsening of CP –1 week to 3 months Biliary obstruction, stricture GI : stomach, intestinal bleeding, obstruction, fistula Chest wall pain , rib fracture Pathological changes Hyperemia Veno-occlusive disease Central venous congestion Atrophy of adjacent hepatocytes 56 SBRT related, site dependent.
  56. 56. Dose – Volume interplay is crucial! • N= 47 with HCC • Median dose : 36Gy/3# • Local control 90% • 11% declined in CP score – if <800cc liver received 18Gy • Need to individualize dose prescriptions! Hyun Son, IJROBP 2010 57
  57. 57. Case study • 58M • ECOG 1 • PMH : DM, hypt, AF, Hep B • Child’s A liver cirrhosis secondary to Hepatitis B • HCC diagnosed Dec 2013, Segment 5 (2.7 x 2.5 x 3.1cm) • AFP 13000+ • Not suited for resection due to high ICG • Underwent TACE x 1 • Post TACE CT showed good response in primary, however showed tumour thrombus of right portal vein. AFP 5000+ • Not a transplant candidate • Not suited for 2nd TACE in view of porto-systemic shunting and tumour thrombus involving main portal vein • Referred for RT 58
  58. 58. SBRT evaluation • CP B-7 • ECOG 1 • Planned for SBRT using VMAT 5 fractions • Already on entecavir 59
  59. 59. Dose selection for SBRT – sliding scale Veff = effective liver volume irradiated ( Liver volume – Gross tumour volume) RTOG 1112 protocol 60 Lee JCO 2009
  60. 60. 61
  61. 61. SBRT (VMAT) 35Gy/5# 62 Courtesy of Dr Leong CN
  62. 62. Take home messages • RT may be a treatment option in patients who are unsuitable for other established local therapies • RT is safe and effective in patients with normal underlying liver function. • Randomized trials of RT in HCC and comparative effectiveness studies of different RT techniques are needed. • Good local control = survival benefit? 63
  63. 63. Thank you • "Better is possible. It does not take genius. It takes diligence. It takes moral clarity. It takes ingenuity. And above all, it takes a willingness to try.” – Atul Gawande • Email: cfsvba@nus.edu.sg 64

×