Latest advances in external beam radiotherapy for hepatocellulalar carcinoma. Presented at "Liver Disease awareness week" 2014 Singapore

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. 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. 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. Radiotherapy dictum
• Dose response seen in tumours and normal
organs
• Maximize therapeutic window (maximum
dose to tumour, minimum dose to normal
organs)
4

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. Radiotherapy is not what it used to
be …
6

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. Liver radiotherapy reports
8
Klein, Dawson IJROBP
2012

9. What are the challenges and
opportunities for RT in HCC?

11. Uncertainty margins
11

12. Ways to address motion
• Image guidance (IGRT)
• Limit motion
• Quantify actual motion
• Track motion
• Treat at certain phases of respiration
12

13. Image guidance then and now…
Positional verification based
on bony contours
More accurate alignment
using on-board cone beam
CT
13

14. MRI-LINAC
14

15. Ways to address motion
• Image guidance
• Limit motion
• Quantify actual motion
• Track motion
• Treat at certain phases of respiration
15

16. Custom vacuum bag
• Customised immobilisation
device to accommodate the
patients entire body
• Immobilisation device can
be mounted onto the
treatment couch
• Vacuum Bag
16

17. Abdominal
compressor
• Useful for abdominal
treatment and lower lobe
lung tumours
• Paddle board applied to
upper abdomen to limit
diaphragmatic motion
17

18. Ways to address motion
• Image guidance
• Limit motion
• Quantify actual motion
• Track motion
• Treat at certain phases of respiration
18

19. 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

20. Ways to address motion
• Image guidance
• Limit motion
• Quantify actual motion
• Track motion
• Treat at certain phases of respiration
20

21. 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

22. Ways to address motion
• Image guidance
• Limit motion
• Quantify actual motion
• Track motion
• Treat at certain phases of respiration
22

23. 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

24. 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

25. Era of conformal RT techniques

26. 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

27. 3D conformal Radiotherapy
• Based on 3D imaging (CT)
• Forward planned
• Multi-leaf collimators used
to shape treatment field
27
JACMP 2013; 14(3)

28. 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

29. 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

30. 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

31. SBRT – Linac based @ NCIS/NUH
31

32. 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

33. 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

34. What is the role of RT in HCC?

35. Multimodal treatment is important
Local therapy
•Resection
•Transplant
•RFA
•PEI
•RT
Loco-regional
•TACE
•SIRS (y-90)
Systemic
•Biologics
•Chemo
35

36. 36

37. 37

38. RT has potential role across all stages of HCC
38
Klein IJROBP 2013

39. RT has potential role across all stages of HCC
39
Klein IJROBP 2013

40. Role of definitive RT in those not suited for surgery, RFA
40
Dawson, ASTRO

41. 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)

42. RT has potential role across all stages of HCC
42
Klein IJROBP 2013

43. 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

44. 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

45. RT has potential role across all stages of HCC
45
Klein IJROBP 2013

46. 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

47. RT trials for HCC with PVT
47
Klein, Dawson IJROBP 2013

48. 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

49. Changes in Liver function post RT
49
months
Bujold, ASTRO 2011

50. RT has potential role across all stages of HCC
50
Klein IJROBP 2013

51. 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

52. 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

53. 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

54. 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

55. • 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

56. 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.

57. 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

58. 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

59. SBRT evaluation
• CP B-7
• ECOG 1
• Planned for SBRT using
VMAT 5 fractions
• Already on entecavir
59

60. Dose selection for SBRT – sliding scale
Veff = effective liver
volume irradiated
( Liver volume – Gross
tumour volume)
RTOG 1112 protocol 60
Lee JCO 2009

61. 61

62. SBRT (VMAT) 35Gy/5#
62
Courtesy of Dr Leong CN

63. 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

64. 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