24° CORSO RESIDENZIALE DI AGGIORNAMENTO con il patrocinio dell’Associazione Italiana di Radioterapia Oncologica (AIRO) Moderna Radioterapia, Nuove Tecnologie e Ipofrazionamento della Dose 17 marzo 2014: Management dell’organ motion nei trattamenti stereo-RT e radiochirurgici: ruolo di fiducials e on-board imaging

1. Moderna radioterapia, nuove tecnologie e ipofrazionamento della dose
Management dell’organ motion nei trattamenti
stereo-RT e radiochirurgici:
ruolo di fiducials e on-board imaging
M. Balducci, V. Frascino, R. Autorino, C. Valentini, M.Ferro

2. Introduction
Stereotactic body radiation therapy (SBRT) refers to an
emerging radiotherapy procedure that is highly effective in
controlling early stage primary and oligometastatic cancers
at locations throughout the abdomino-pelvic and thoracic
cavities, and at spinal and paraspinal sites.
Benedict et al.: Stereotactic body radiation therapy: The report of TGT101, 2010

3. Radiobiology of SBRT
• Delivering a few fractions of large dose in
relatively short overall treatment time results
in a more potent biological effect.
• The clinical outcomes of SBRT for both
primary and metastatic diseases compare
favorably to surgery with minimal adverse
effects.
Timmerman, Semin. Radiat. Oncol, 2008
Timmerman, Ca-Cancer J. Clin., 2009
Grills, J. Clin. Oncol, 2010

4. Characteristics of SBRT
Ablative dose fractionation delivered to the patient with
subcentimeter accuracy.
Timmerman, JCO, 2007
Risk of target missing
• OAR Dose
• Target Dose

5. Management Organ Motion
Timmerman, JCO, 2007
1. Immobilization  Dampening
2. Gated Radiotherapy
- Breath-Hold techniques
- Optical tracking techniques
- Respiratory gating techniques
3. CBCT

6. Immobilization
Frame-based Frameless
• ExacTrac® X-Ray 6D system
(Brainlab AG, Germany)
• FOCAL unit (fusion of CT and
Linac)
Stereophotogrammetry
method for determining the
3D position of an object from
multiple 2D images

7. Motion control
Dampening
Abdominal Compressor

8. Motion control
Dampening
Thoracic Compressor

9. BREATH-HOLD TECHNIQUES
DIBH : DEEP INSPIRATION BREATH-HOLD
Is generally performed in deep inspiration
o Physiologically easier to mantain
VOLUNTARY BREATH-HOLD
A spirometer indicates in real-time the desired level of breath-hold and the level
actually achieved.
The patient breathes freely for a certain numbers of cycles and then performed a
modified manoeuvre inflate his lungs and mantain breath-hold in the desired zone,
determined in collaboration with patient during a training session.
ACTIVE BREATHING CONTROL (ABC) SYSTEM
Breath-hold is not manteined voluntarily by the patient but is forced.
When the patient enters the desidere breath breath-hold zone, a baloon catheter
or a valve completely closes the air inlet.

10. Optical tracking techniques
Real time localization of a constantly moving
tumor
EXTERNAL TRACKING
Tumor position is derived from SURROGATE BREATHING
SIGNALS such as LUNG VOLUME or SKIN MOTION
Disadvantages
The short-term correlation between external surrogates and internal target
position may be not stable during a long treatment fraction and over the
treatment course

11. INTERNAL TRACKING
• Implanting of FIDUCIAL MARKERS in the tumor-bearing
organs. The high radio-opacity of the markers makes them
readily detectable in fluoroscopic images.
• Markers can be implanted either
PERCUTANEOUSLY or
ENDOSCOPICALLY.
Disadvantages
• Invasive procedure
Jiang et al, Seminars in Radiation Oncology 2006
Optical tracking techniques

12. Respiratory gating techniques
End exhale
End inhale
0%
100%
Amplitude
Gatingwindow
Giraud P, et al. Reduction of organ motion effect in IMRT and conformal 3D radiation delivery by using gating
and tracking techniques. Cancer Radiothérapie 10, 269-282.

13. Image-guided localization
Electronic Portal Imaging Device (EPID)
Bones

14. Image-guided localization
3D volumetric images:
Cone Beam-CT (CBCT)
SOFT TISSUE

15. Selections of the patients:
• Dimensions of GTV (< 100 cm3)
• T (peripheral)
•N0(and with low risk of subclinic N)
• Good compliance
T1-2 (< 5 cm)
N0
peripheral
unresectable
SBRT and SRS in LUNG
CANCERS

16. SBRT and SRS in LUNG
CANCERS
 Inferior tumors move more superior tumors
The largest axis of motion is in the SI direction
 Mediastinal lymph nodes are also subject to a significant
degree of tumor motion
Median change ML: 0.4 mm
Median change SI: 1.0 mm
Median change AP: 0.4 mm

17. Increase precision
Breathing adaptation
Image guidance
Reduce margins
Dose escalation
Explore different IPOfractionation schedule
HOW TO MOVE ON…….

18. T
TO REDUCE ORGAN MOTION DURING
SBRT AND SRS IN LUNG CANCERS
ABDOMINAL COMPRESSION
BREATH HOLD
GATING
TRACKING

19. REDUCTION OF ORGAN MOTION:
ABDOMINAL COMPRESSION
Heinzerling J.H. et al, IJROBP 2008
MC and HC vs NO Compression:
LL p=0.02
SI p< 0.0001
Overall p< 0.0001
HC vs MC:
SI p= 0.04
DISADVANTAGES:
- Patient discomfort
- Decreased daily reproducibility
- Girth
- Respiratory effort

20. Breathing Adapted Radio Therapy
B-ART
Breath-Hold
Controlled
Breath-hold
Voluntary
Breath-hold
Free-breathing
Moving-beam
(TRACKING)
Free-breathing
Gating
Free-breathing
Synchronisation
REDUCTION OF ORGAN
MOTION…….

21. REDUCTION OF ORGAN MOTION:
BREATH HOLD
Giraud P. et al, Cancer/Radiothérapie 2006
Hanley J et al, IJROBP 1999
Kim DJ, IJROBP 2001
Voluntary Breath-Hold
 Intra-Breath-Hold Reproducibility: 1.0 + 0.9 mm
Inter-Breath-Hold Reproducibility: 2.5 + 1.6 mm
Reduction of margins : 0.75-0.5 mm
 Mean Residual diaphragm movements:
0.97 mm over one fraction
<5mm troughout treatment

22. REDUCTION OF ORGAN MOTION:
BREATH HOLD
Giraud P. et al, Cancer/Radiothérapie 2006
Wong JW et al, IJROBP 1999
Active Breath-Hold
Residual intra-fraction diaphragm movements: 1.5 + 1.8 mm
Residual inter-fraction diaphragm movements : 4.0 + 3.3 mm

23. REDUCTION OF ORGAN MOTION:
BREATHING SYNCHRONIZED RADIOTHERAPY
GATING
Rationale:
- Letting the beam switch with breath
How:
- By using surrogate for tumor motion
- Spirometry: flow or temperature sensor
- Chest or abdominal wall motion (external system, diaphragm..)

24. REDUCTION OF ORGAN MOTION:
BREATHING SYNCHRONIZED RADIOTHERAPY
“RGRT seems to be essential to reduce toxicities, expecially the pulmonary, cardiac
and esophageal late toxicities with the DIBH methods”.
Giraud P, Journal of Thoracic Oncology 2011
 401 pz
 3 TC: free-breathing, deep inspiration breath hold, 4D TC

25. REDUCTION OF ORGAN MOTION:
BREATHING SYNCHRONIZED RADIOTHERAPY
Paumier A et al, Cancer/Radiothèrapie 2012
7 pts
11 lesions
3 TC: free-breathing, deep inspiration breath hold, 4D
5 PT: free-breathing, deep inspiration breath hold
from 4D TC: two breathing syncrhronized treatments
(inspiration and expiration), ITV

26. REDUCTION OF ORGAN MOTION:
BREATHING SYNCHRONIZED RADIOTHERAPY
Paumier A et al, Cancer/Radiothèrapie 2012
Mean PTV with free-breathing modality was
greater than any of the other tecniques (p< 0.0001)
PTV with ITV was reduced by one quarter (63+31 cm3)
PTV with breathing tecniques was reduced by one third (50 to 54 + 24 to 26
cm3)
Deep inspiration led to significantly increase the healthy lung volume mean
volume of 5500 ± 1500 cm3 versus 3540 to 3920 cm3 (p < 0.0001)
Deep inspiration breath hold led to the lowest V5 and V20
Deep-inspiration breath-hold technique provides the most significant dosimetric
advantages: small PTV and large lung volume.
4-dimensional CT allows for a personalized and reduced PTV compared to free-
breathing CT.

27. REDUCTION OF ORGAN MOTION:
BREATHING SYNCHRONIZED RADIOTHERAPY
Paumier A et al, Cancer/Radiothèrapie 2012

28. REDUCTION OF ORGAN MOTION:
TRACKING
Rationale:
-Letting the beam move with the target
How:
- By using surrogate for tumor motion:
- External or internal fiducials
- Prediction algorithms
CyberKnife®
Real time tracking radiotherapy Dynamic MLC
Synchronized Moving Aperture
Radiation Therapy SMART®

29. REAL TIME TUMOR TRACKING:
FIDUCIALS
 Size: 0,8 x 5 mm
0,8 x 3 mm
 Percoutaneously using TC
 Broncoscopy
 At least 3 fiducials for centrally located tumors
 4-5 fiducials in peripheral tumors

30. REAL TIME TUMOR TRACKING
109 pts
Dose: 40-48 Gy in 4 fractions
1.5 mm gold markers were implanted near
the tumor by bronchoscopy
 Median FUP: 25 months
5-ys OS: 64%
5-ys LC: 78%

31. REAL TIME TUMOR TRACKING
Radiation Pneumonitis G2: 15 pts (13.8%)
Radiation Pneumonitis G3: 3pts (2.8%)
Radiation Pneumonitis G4-5: 0 pts (0.0%)
P=0.02
P=0.003
SBRT using the RTRT
system achieved very low
incidence of RP: the small
MLD and V20 irrespective
of tumor amplitude

32. FIDUCIALS ?
 Pneumothorax
 Pulmonary artery embolization
 Infection
 Displacement
 Misaglignment during the respiration cycle
Misalignment of ≥2.5 mm did not
occur in cases with an initial
marker/tumor distance of ≤2.5 cm
Yamazaki Rie at al, Rdaiation Oncology 2012

33. 7 lung cancer patients
Bronchoscopic implantation of the radiofrequency transponders
concurrently with implantation of the fiducials (to improve stability and
fixation)
2-3 transponders for patient
Large variations from fraction to fraction within a single patient
Both transponder and tracking system are still necessary to create a clinical daily-use
system to assist with actual lung radiation therapy.
REAL TIME TUMOR
TRACKING

34. SBRT and SRS in LUNG
CANCERS
RTRT reduces the toxicty
TRACKING achieves low incidence of radiation
pneumonitis
 No comparative studies
?

35. Organ motion in liver tumor
Single/oligomet tumors Primary tumors (1-3 lesions)

36. Local Management of Hepatic Lesions
• Surgery
– Resection
• +/- Preoperative Chemotherapy (Systemic and HA)
• Interventional Radiology
– Radiofrequency Ablation
– Cryoablation
• Radiation Oncology
–Stereotactic Body Radiation Therapy

37. THE RADIOTHERAPIST ONCOLOGIST
CHALLANGE
Liver not only moves…but the lesions are often difficult to be identified
on planning CT and CBCT….

38. SBRT in liver tumor:
How much does liver move?
30mm

39. Active
Breathing
Coordination
(ABC)
Abdominal
Compression
(AC)
Respiratory
gating

41. Simulation
•CTV=GTV+3-5mm margin
•PTV=CTV+8mm in ML and AP, and 8mm (in not diaphragm movm in
fluoroscopy) or 10mm (if diaphragm movm in fluoroscopy ) in CC
Inter-intrafraction
error
•Interfraction error: pretreatment CBCT aligned with simulation CT
by manual registration, error in 3 directions (ML, AP, CC) obtained
and corrected if ≥5mm
•Intrafraction error: acquisition of post-treatment CBCT to evaluate
reproducibility of liver through treatment course
Pt positiong error
•To evaluate the effect of pt positioning on liver positioning error, off
line manual bony aligment of spinal vertebrae (defined the same as
liver positioning error)

42. Liver RT with long time breath-holding at end-inhale is an effective method to reduce liver
motion, PTV and dose to normal tissue. There are considerable interfraction and
intrafraction errors of liver positioning using ABC breath-holding for long time at end-
inhale. CBCT guided online correction of positioning errors is reccomended for liver
radiotherapy with end-inhale ABC
Interfraction motion
Intrafraction motion
Definition of CTV-PTV margin (<1-2mm)
Liver positioning error
Patient positioning error

43. Daily IGRT using orthogonal kV
imaging with or without kVCBCT was
performed. Fluoroscopic projection
were acquired immediately prior to
treatment to confirm respiratory
motion magnitude under AC.
Offline evaluation was performed on
CBCT scans

44. For each available CBCT scan, CBCT scan was exported to TPS,
where manual rigid liver-to-liver registration to planning CT scans
were perfomed. After registration CBCT livers were contoured by a
single operator. Once liver contours were completed, they were
exported to MORFEUS (deformable registration tool)
Interfraction spatial differences of the liver surface was
performed using MORFEUS to determine whether the liver
shape was reproducible as a whole and whether there were
trends in liver shape variability from day to day.
The GTV was delineated by an experienced radiation oncologist on
contrast-enhanced planning CT scans. Using MORFEUS, a COM
(Center Of Mass) displacement of each GTV was determined for
each available CBCT scan, based on the liver deformation after rigid
liver-to- liver registration.
A limitation of CBCT liver tumor position evaluation is the inability to visualize
the tumor on CBCT. To overcome this, tumor motion was predicted by use of
a COM displacement after deformable registration of the liver at each
fraction

46. Phase I dose escalation study on feasibility and safety of treating primary met liver tumor (diameter ≤5cm)
with single fraction SBRT (from 18Gy to 30Gy at 4Gy increments with planned maximum dose of 30Gy)
Simulation
•Implantation of 3-5 gold fiducials seeds, into or close to the target
•To correct for respiration-related deformation and rotation ts had a 4D-CT scans
•Intravenous contrast was administered
Target
definition
•GTV contoured on the various respiratory phases
•ITV=union of the GTVs defined on the arterial phase scan as well as the end-expiratory scana and
the end-inspiratory scan from 4D-CT.
•CTV=GTV
•PTV=CTV+3-5mm to the ITV
Dose
escalation
•At least 3 pts completed treatmentt and received 12 wks follow-up toxicity assessment before
escalating dose level (acconting for acute and subacute tox)
•If Grade 3 (Dose Limiting Toxicity) or higher tox were encountered, an additional 3 pts would
have been accrued at that dose level
•Maximum tolerated dose was defined as >50% of pts experiencing DLT (≥Grade 3 tox occurring
within 60 days of treatment)

47. 64,3% 50,4%
It is feasible and safe to deliver single
fraction, high dose SBRT to primary or
met liver malignancies measuring ≤5cm.
Single fraction SBRT promising tumor
control with minimal acute and long-term
tox. SBRT appears to be a viable non
surgical option, but further studies are
warranted to evaluate both control rates
and impact on quality of life.

49. Purpose: REALIABILITY OF LIPIODOL (in terms of change of volume and shape of retained liodol) for CBCT
image guidance in RT for pts with unresectable liver tumors after TACE. The potential of MARGIN REDUCTION
with this image-guidance was also discussed.
TP: simulation with ABC,
contouring of GTV which
included the volume of
lipiodol; CTV=GTV+8mm
PTV=CTV+5mm in ML and
8mm in CC and AP
direction
46 pts with 1
solitary tumor
in liver.
2 CBCT acquired
(1 before and 1
after treatment)
to evaluate inter
and intrafraction
errors.
• Shape of Lipidol retention was
calculated using Dice similarity
coefficient (acceptable if >0,7)
comparing planning CT and
post-treatment CT
• Influence of lipiodol on dose
distribution

50. Results
• Mean Dice similarity coefficient=0,836
• The lipiodol retention volume measured on pre-
post treatment CTs images presented minimal
chages through RT.
• The volume of lipiodol up to 10ml did not
significantly change the dose (roughly 1,5% for
6MV and 15 MV beam energy)
• Reduction of the average individual pt random (σ)
set-up error
• Reduction of CTV-PTV margins.

51. ML=3,4->1,8mm
CC=6,6->3,1mm Average individual pt
random (σ) set-up error
ML=5,4->2,5mm
CC=6,8->2,9mm
Reduction of CTV-PTV
margins.
CONCLUSIONS: Lipidol was succesfully used as a direct surrogate for CBCT image guidance
in RT of liver cancer. Combination of ABC and CBCT image guidance with lipidol is
promising in improving the accuracy of target localization and can potentially reduce CTV-
PTV margin in liver tumor RT.

52. Conclusions
• At the moment there is not the presence of
the «Best» strategy to be used accounting for
organ motion
• Fiducials and new strategies (Lipiodol) seems
promising for target localization.

53. SBRT
in Prostate cancer
Rationale: ↓ α/β ratio = 1,5 Gy
High sensitivity to dose per fraction
Advantageous Hypofractionation
Brenner, Int J Radiat Oncol Biol Phys, 1999

54. Management Organ Motion
↓ bladder and rectal toxicity
CyberKnife
Fiducial markers
SBRT
in Prostate cancer

55. Xie, Int. J. Radiation Oncology Biol. Phys, 2008

56. Fiducials markers
• 24 carat gold
• 1mm in diameter by 5mm in length
• Markers are implanted in the prostate base, apex and
contralateral midzone, and placed away from the urethra.

57. Disadvantage
of fiducial implantation
Little information on
• deformation of the target
• localization of the seminal vesicles
• changes in surrounding normal anatomy
Shinohara, UROLOGY, 2008.

58. On Board Imaging

59. Fiducials vs OBI
256 datasets – 16 pt

60. Fiducials vs OBI
Matherial and Methods
•MV images with fiducial markers  MVFM
•CBCT images with fiducial markers  CBCTFM
•CBCT images with suppression of fiducial markers signals to allow for soft tissue
matching  CBCTST

61. Fiducials vs OBI
MD
LR: 0.8mm;
AP: 0.2mm;
SI: 0.8mm

62. Conclusions
• CBCT is feasible for daily online image
guidance of the prostate.
• Markers may not be the best method to test
CBCT against, as they are a surrogate for daily
prostat position.
• Additional information provided by CBCT:
target visualization, critical organ avoidance.

63. Fiducials vs OBI
286 datasets – 36 pt

64. Fiducials vs OBI
Matherial and Methods
•kV portal images with fiducial markers  kVFM
•CBCT with suppression of fiducial markers signals to allow for soft tissue
Matching  CBCTST

65. Fiducials vs OBI
MD: 3,4 mm
MD: 1,6 mm
MD: 3,1 mm

66. Conclusions
• «The most likely factor resulting in shift differences between
imaging modalities is that CBCT images of the prostate region
are not of a sufficient quality to allow for consistent,
reproducible identification of the borders of the prostate»
• «Our insitution has opted to continue to use fiducials with kV
imaging for daily prostate IGRT. We avoid prolongation of
patient treatment time, patient exposure to additional
ionizing radiation from CBCT, and uncertainty associated with
CBCT soft-tissue definition»