2. Historical Background
The first one to combine stereotactic
methodology with radiation therapy was the
Swedish neurosurgeon Lars Leksell.
Leksel performed the first treatment in 1951, at
the Karolinska Institute, and called the new
therapy approach radiosurgery (RS).
Leksel continued his work and built the first
isotope radiation machine, in 1968, the
Gamma knife.
Swedish physicist Larsson proposed to use the
LINAC instead Co 60 or protons (Larsson et
al. 1974) in early 80’s.
3. INTRODUCTION :
Stereotactic refers to using a precise three-dimensional
mapping technique to guide a procedure.
The term stereotactic radiosurgery (SRS) is used for
stereotactically guided conformal irradiation of a defined
target volume in a single session.
The term stereotactic radiation therapy (SRT) refers to
stereotactically guided delivery of highly conformal
radiation to a defined target volume in multiple fractions,
typically using noninvasive positioning techniques.
4. The term fractionated stereotactic radiosurgery (FSR) is limited
to stereotactically guided high-dose conformal radiation
administered to a precisely defined target volume in two to
five sessions.
Stereotactic Radiosurgery (SRS) :
– SRS is a precise and focused delivery of a single, high dose of
irradiation to a small and critically located intracranial volume
while sparing normal structure.
Stereotactic Body Radiation Therapy (SBRT) :
– SBRT is a treatment procedure similar to SRS, except that it
deals extra-cranial radiosurgery.
5. SRS and SBRT feautures:
1. High doses of radiation via multiple beams.
2. Limited number of treatment session (1-5).
3. Image guided treatment (CT, PET, MRI).
4. Computer assisted robotic delivery.
5.Real time motion management.
6. The challenge for SRS and SBRT is to accurately
deliver conformal high dose radiation to the
target and minimize normal tissue damage.
9. Radiation: Fractionation
• Standard fractionation:
– 1.8-2.0 Gy a day, 5 days a week for 25-30 treatments
• Conventional hypofractionation:
– 3-5 Gy a day, 5 days a week for 10-15 treatments
• Stereotactic radiotherapy:
– 5-25 Gy a day, 1-3 days a week for 1-5 treatments
11. Effective SBRT
3. Steep Dose Gradient
30
50
20
10
70
90
100
Within mm outside the
target periphery the dose
become insignificant
Within the target periphery
the dose increases from 50%
to 100% resulting into
inhomogeneous dose
distribution
1. Small Target usually tumor <3cm
2. Highest degree of conformality.
12.
13. Linear = Quadratic
D = D2
D2
/D
D
So can be defined as the dose at which
contribution by single hit (Linear) kill becomes equal
to double hit (Quadratic) kill.
Linear Quadratic model (LQ Model)
Linear Hit ( cellkill)
SF
Dose
Kill
Kill
Quadratic Hit( cellkill)
14. / = 1Gy to 7 Gy (3Gy)
Responsible for late effect of radiation
Eg. Spinal cord, urinary bladder, kidney,
liveretc.
/ = 6Gy to 15 Gy (10Gy)
Responsible for acute effect of radiation
Eg, skin, mucosa, lining of intestine,bone
marrow etc.
D =
D =
SF
Shoulder is more curvy
Shoulder is lessCurvy
Late Reacting Tissue Early Reacting Tissue
Ratio defines “curviness” of survival curve
Based on ratio, the body tissues
have been divided into two category.
Average / ratio of malignant tumor is taken as 10
Dose Dose
15. Dose(Gy)
SF
Effect of high dose on Cell Survival Curve
1
.1
.01
.001
.0001
Same dose increment result in
much higher reduction in SF in high
dose region than in low dose
region.
In low dose region, radiation is
less damaging while in high dose
region it is more damaging.
First Principle
High dose per fraction is
more tumoricidal and is
more damaging
1 3
Low Dose Region
15 17
high DoseRegion
16. SF
Dose
Dose
Non Fractionated RT More Effective For Benign Tumors
Tissue with low value
Benign Tumor like AVM,
Meningioma etc
10
3
Second Principle
High dose per
fraction is more
damaging to Benign
lesions with low
value like
meningioma, AVM,
acoustic neuroma
etc
D1 D2
Tissue with high value
MalignantTumors
17. Tumor
Normal
Third Principle
This is overcome by highly
precise, highly conformal RT
with min surrounding normal
tissue in high dose clouds
Red Shell
NonFractionatedRT More Damaging to Late Reacting Tissues
19. G
T
V
C
T
V
P
T
V
70 Gy/35fx/2Gy per fx
For surrounding normal tissue we
generalize a safe BED 100 Gy3 (60Gy/30F)
64 Gy in 35fx, d/f = 1.8 Gy
BED = 64(1+1.8/3) = 102 Gy3
Clinical Significance of Red Shell
70Gy
60Gy
Tolerance Dose
NORMAL TISSUE
<60 Gy
Dose
Distance from centralaxis
Fractionated Radiotherapy
Red Shell
20. G
T
V
C
T
V
P
T
V
Clinical Significance of Red Shell
48
29Gy
Tolerance Dose
NORMAL TISSUE
<100 Gy3
Dose
Distance from centralaxis
Non Fractionated Radiotherapy
Dose = 12Gy X 4
For surrounding normal tissue we
generalize a safe BED 100 Gy3 (29Gy/4F)
Red Shell
8 Gy X 4 = 32 Gy
BED = 32(1+8/3)
= 118 Gy3
Thickness or volume of the red shell
to be kept as minimum as possible
Red Shell effect
is significant in
non fractionated
RT and not in
fractionated RT
21. • So we can reduce the Volume of Red Shell
thus damaging effect of Non fractionated RT
on normal tissue by:-
Keeping the dose gradient very steep.
By multiple non-coplaner beams and careful planning
Keeping the target volume minimum.
By Treating early lesions only
Reducing the PTV margins.
By Reducing uncertainties. Use of IGRT, 4D RT, gamma
knife etc
Delivering total dose in more than 1 fraction.
By using 2-4 fractions
Red Shell
22. 4 Rs of Fractionations
• Re-oxygenation
• Repair of Sub-lethal damage
• Re-population
• Re-distribution
23. D1 D2 D3 D4
SF
Dose
Effect of Oxygen on cell survival curve
Oxic
Decreasing Oxygen concentration hypoxic
Bigger the Tumor More is the
hypoxic component & vice versa
Third Principle
Treating the small
tumors by non
fractionated RT as they
are relatively well
oxygenated with little
hypoxic fraction.
25. 1
.1
.01
Cell Survival Curve of
mixed population of
cells(oxic and Hypoxic)
SF
Oxic
hypoxic
Hypoxic
Transitional Zone
Non Fractionated RT
Principle:- Hypoxic fraction is also depopulated due to
direct damaging effect of very large dose per fraction.
2 4 6 8 10 11 12 13 14 15 16 17 18 19 20
Dose (Gy)
26. The ratio of HYPOXIC to AEROBIC IR doses needed to
achieve the SAME biological effects is called Oxygen
Enhancement Ratio.
OER = D0 (hypoxic)
D0 (aerobic)
6 Gy
2 Gy
= 2.5 to 3 for x-rays and -rays
SRS/SRT Dose is > 12 Gy
27.
28.
29. Non Fractionated RT
Intra Fraction Repair with T1/2 = .2 -.4 hr may occur
during SBRT as treatment time is prolonged
Duration of Single Fx (Hours)
20 Gy
T 1/2 =0.4h
A
1 2
B
T1/2 =0.2h 20 Gy
1 2
Late Reacting Tissue
Positive effect
on
normal tissue
As the treatment
duration increases the
bio effective dose
reduces
Faster the repair more
the loss of BED
30. Repopulation(NSCLC)
Without Repopulation
Ca Lung
With Repopulation
Repopulation does not compromise
the outcome in SBRT
Repopulation in NSCLC starts at 28 days
Most of the SBRT lung regimen are completed by
two weeks
31. SF
Dose
Effect of cell cycle on cell survival curve
G2, M
G1 Early S
Late S
G2, M-> most sensitive
Late S -> most resistant
Redistribution.
32. Non Fractionated RT
Benign Tumors not a issue like AVM or
meningioma as they are not actively proliferating
Malignant Tumors may have negative
effect but over come by very large dose of non
fractionated radiotherapy.
G2, M-------Most sensitive
Late S--------Most Resistant
There is 5 fold difference
in survival after 200 rad
D0 is 2 Gy
D0 is 10 Gy
SRS/SRT Dose is > 12 Gy
33. New Biology of High dose RT
• Vascular damage at high dose.
• Stem Cell death at high dose.
34.
35. Vascular density in experimental tumor irradiated with high dose per fraction
Pre RT
Post RT
Human Melanoma
Human Ovarian Ca
High dose RT
Pre clinical Evidence
38. Stem Cell Death
CD 133+ Glioma cells are relatively radioresistant
CD 44+ breast cancer cell lines
39. Cell death at High Dose RT
• Direct cytotoxic damage related to DNA
damage seen at all dose level and explained
by LQ model
• Vascular/ stromal damage triggered at high
dose level.
• Stem Cell Death triggered at high dose level.
•Loss of Autocrine Paracrine Growth factor as a
result of massive destruction of the tumor cells
by high dose of RT as established in ca lung.
40. SBRT PHYSICS AND
TECHNOLOGY
1. CT simulation: Assess tumor motion
2. Immobilization: Minimize motion, breathing effects
3. Planning: Small field dosimetry considerations
4. Repositioning: High precision patient set-up:
Fiducial systems, IR/LED Active and Passive markers, US, Video
5. Relocalization: Identify tumor location in the treatment field:
* MV/ KV Xray, Implanted markers and/or set-up fiducials
* Motion tracking and gating systems
* Real-time tumor tracking systems with implanted markers
6. Treatment delivery techniques
Adapted conventional systems
Specialized SRT: Novalis, Cyberknife, Trilogy
41.
42. 4D CT Simulator
A technique that allow an
evaluation of the
motion of the target
Figure: Christopher Willey, MD, PhD
43. 4D CT Simulator
The trace of the target motion
allow the creation of a
internal target volume
(ITV) for treatment
planning
45. • Breathing-related motion control devices and systems fall into
three general categories:
(a) dampening,
(b) gating, and
(c) tracking or “chasing.”
46. Respiratory dampening techniques
• Include systems of abdominal compression intended to
diminish one of the largest contributors to breathing-related
motion, namely diaphragmatic excertion.
47. ABC:
• Also included in this category are the systems employing
breath-holding maneuvers to stabilize the tumor in a
reproducible stage of the respiratory cycle (e.g., deep
inspiration).
48. Gating systems for SBRT
• It follow the respiratory cycle using a surrogate indicator for
respiratory motion, for example, chest wall motion, and
employ an electronic beam activation trigger allowing
irradiation to occur only during a specified range of expected
tumor locations.
49.
50.
51.
52. How LINAC Radiosurgery Works :
The gantry of the LINAC rotates around
the patient, producing an arc of radiation
focused on the target.
The couch in which the patient rests is then rotated in
the horizontal plane, and another arc is performed.
In this manner, multiple non coplanar arcs of radiation
intersect at the target volume and produce a high target
dose, resulting in minimal radiation affecting the
surrounding brain and normal tissue.
53. How Gamma Knife Radiosurgery Works:
The GammaKnife is used to treat brain tumors. The
procedure begins with the patient receiving anesthesia
and a frame is attached to the head to hold it in place.
The patient lays on their back and moved head first into
the machine, where 201 beams of cobalt – 60
radiation target the diseased tissue, without
damaging the surrounding tissue.
54. Recent Advances in SBRT and SRS
VMAT
Volumetric Modulated Arc Therapy (VMAT)
was first introduced in 2007 and described as a
novel radiation technique
VMAT is the simultaneous variation of three
parameters during treatment delivery, i.e. gantry rotation
speed, treatment aperture shape via movement of MLC
leaves and dose rate
55. Recent Advances in SBRT and SRS
Flattening Filter Free (FFF) mode
FFF beam is produced without the use of
flattening Filter
In the 1990s, several groups studied about FFF
high-energy photon beams. The main interest
for that, is to increase the dose rate for
radiosurgery.
Need of increase in dose rate from traditional
300-600 to 1400-2400MU/min to overcome
time-inefficiency and to improve patients
comfort specially in SRS/SBRT
56. Dosimetric advantages of FFF beams
FFF has increased dose rate, e.g., 1400 MU/min for 6 MV, 2400
MU/min for 10 MV.
FFF beams have less variation of off-axis beam hardening.
FFF has less photon head scatter and thus less field size
dependence.
FFF has less leakage outside of beam collimation
57. Potential advantages of FFF beams
Fast treatment for Stereotactic Radiotherapy (SRT) and SRT
plans between FB and FFF beams should be similar for
small fields.
FFF is especially useful for SBRT, where respiration
controlled treatment delivery is compromised by the large
number of MU to delivery high fraction doses.
Patient beam on time can be reduced for IMRT
58.
59. Dosimetry concern of FFF
• The Dosimetric parameters like field size definition, beam
quality, surface dose, off axis ratio , flatness, symmetry, degree
of un-flatness, penumbra and depth dose profiles differs from
standard Linac with Flat beam.
• There is no international standard/acceptance test protocol
available for FFF beam, AERB constituted a Task Group to
evolve the acceptance criteria for FFF beam
60. AERB Recommendations for FFF
Treatment should be implemented with TPS
through Record & Verify system, Manual planning and
calculation shall not be adopted in clinical use of FFF beam.
61. AERB Recommendations for FFF
Measurements should cover
Beam Energy:
TPR20/10 for 10 cm x 10 cm Field Size for all FFF energies
Surface dose:
10cm x 10cm and 20cm x 20cm compared with the corresponding
nominal flat beam energy
OAR
At ±3 cm from central axis at the depth of 10 cm for 10 cm x 10 cm
collimator setting shall be measured for all available FFF energies
62. AERB Recommendations for FFF
Depth dose profiles
Dose profile for field size 5cm x 5cm, 10cm x 10cm and 20cm x
20cm at depth of Dmax and 10cm shall be recorded for all
available energies.
FS 10 cm x 10 cm, the Dosimetric parameters such as field size,
penumbra, flatness, symmetry shall be measured and evaluated
the methods applied for flat beam
If flatness is > ± 3%, the evaluation criteria of unflattend beam
shall be adopted
63. Depth dose profiles
Flatness: As per IEC 976 (IEC
60976), the flat region for
field sizes less than 10cm x
10cm along major axes
defined by subtracting 1cm
from the beam profiles.
Eg. For F.S 5cm x 5cm flat
region is central 3cm.
64. Depth dose profiles
Inflection Point: Inflection Point
can be identified as per its
mathematical definition.
However, for practical purposes it
can be approximated as the mid
point on either side of the high
gradient region (sharply
descending part) of the beam
profile.
Penumbra:Lateral Separation
beween either side of profile will
be measured for the penumbra
65. Degree of un-flatness:
• To quantify the degree of unflatness, lateral distance from the
central axis at 90%, 75% and 60% dose points on either side of
the beam profile shall be recorded along major axes.
66. Comparison of FFF and FB for SBRT
Similar Dose distribution and DVH for FB and FFF
Treatment plan strategies are similar between FB and
FFF beams since the beam profile are similar for field
size < 4 cm
67. AAPM TG 101 Recommendation for SBRT
SBRT Patient Selection Criteria:
When appropriate protocols are not available, clinicians must decide
whether they will treat patients in accordance with published guidelines
or develop new SBRT guidelines. At a minimum, an institutional
treatment protocol or set of guidelines should be developed by
radiation oncologists and physicists.
Simulation imaging:
The simulation study should cover the target and all organs at risk to
obtain geometric and Dosimetric information for the treatment setup
Slice thickness: < 3 mm near clinically important organs
68. AAPM TG 101 Recommendation for SBRT
Planning Recommendation:
The adequacy of target margins i.e., GTV, CTV, ITV, in SBRT
should be based on from information in the current literature
available
Dose Calculation Algorithm:
Algorithms that account for 3D scatter integration such as
convolution/superposition have been found to perform
adequately in most clinical situations, including in many cases
circumstances where there is a loss of electronic equilibrium
such as the lung tissue interface or tumor margin in low-
density medium.
69. Dose Planning
• Concepts in Planning
– Conformality
• Maximum dose to target,
minimum dose to surrounding
tissues
• Achieved by multiple isocenters,
arc weighting, single arcing, arc
spacing and collimator size
• Sphere packing
• Minimum collimator 5 mm
– Treat to the 80% isodose line to
maximize dose fall off
– When multiple isocenters used treat
to the 70% isodose line to avoid
hotspots
70. What do we treat with radiosurgery?
• Brain metastases (up to 4 usually)
• AVM
• Vestibular Schwannoma
• Meningioma
• Recurrent GBM
• Trigeminal Neuralgia
• Spinal Radiosurgery
• Others: Pituitary adenoma, Hemangioblastoma,
Nasopharyngeal carcinoma
72. Brain Metastasis
• UF 12 year experience from 1989 - 2001
• 393 patients
• Types by frequency: lung, melanoma, breast, renal,
GI
• Actuarial 1 year local control rate was 75%
• Median actuarial survival was 9 months
Ulm et al, Neurosurgery 55: 1076-1085, 2004
73.
74. AVM
• UF experience with AVM from 1989-1999
– 269 patients reviewed
– For lesions less than <1 cc, 87.9 % radiological success
• Submitted, UF experience with large volume AVMs
from 1989 - 2005
– 90 patients reviewed
– 70% success rate with repeat radiosurgery
Bradshaw et al, Neurosurgery 52:296-308,2003
75.
76. Vestibular Schwannoma
• UF experience from 1988 to 1998
• 149 patients treated
• Overall radiological tumor control rate was 93%
• Median followup 36 months
• 5 year actuarial control rate was 87%
• At lower doses (12.5 Gy) the incidence of facial and
trigeminal neuropathies fell from 29% to 5 and 2%,
respectively
Foote et al, J Neurosurg 95:440-449, 2001
77.
78. Meningioma
• UF experience from 1989-2001
• 201 patients treated
• Actuarial local control for benign tumors
– 100 % at 1 and 2 years, 96% at 5 years
• Actuarial local control for atypical tumors
– 100% at 1 year, 92% at 2 years, 77% at 5 years
• 6.2% temporary complication rate, 2.3% permanent
complication rate
Friedman et al, J Neurosrg 103:206-209, 2005
79. Glioblastoma Multiforme
• RTOG-9305: Prospective randomized trial designed to
evaluate upfront SRS followed by RT with BCNU compared
to RT with BCNU
• 186 patients enrolled
• Median survival for the two arms was 14.1 and 13.7 months
• No difference in survival with upfront radiosurgery
80. Glioblastoma Multiforme
• UF 12 year experience from 1989-2002
• 100 patients
• Decreased survival for Class I/II,
• Similar survival for Class III/IV
• Increased survival for Class V
• Some role for radiosurgery in recurrent GBM
Ulm et al, Neurosurgery 57:512-517, 2005
81.
82. Spinal Radiosurgery
• Initial treatments with
Cyberknife
• Patient immobilized on
the couch, implantation
of fiducials, followed by
localizing orthogonal
xrays
– University of
Pittsburgh
experience, 2004
• 125 patients treated
83.
84.
85. Cyberknife Outcomes
– Intradural extramedullary lesions (schwannomas,
neurofibromas, meningiomas)
• Stanford experience 1999 - 2004: 51 patients
treated
• 3/51 required surgery within one year because
of worsening symptoms
• 28/51 have at least 24 months followup, 61%
are stable in size, 39% are smaller in size
Dodd et al, Neurosurgery 58:674-85,2006
86. Trigeminal Neuralgia
• University of Wisconsin LINAC Experience
– 28 patients treated with single fraction of 80 Gy to
the trigeminal nerve root (treatment time 55
minutes)
– 57% had complete pain relief, 75% had some
reduction in pain to 3 or less (out of 10)
– Median time to pain relief was one month
Mehta et al, Neurosurgery: 57:1193-2000, 2005.
87. Clinical Experience with Stereotactic Body Radiation
Therapy in Selected Sites
1)Lung
2)Liver
3)Spine
4)Prostate
5)Pancreas
90. • One important observation from the Indiana
University studies was that although the treatment
was generally well tolerated,
• tumor location near large airways in the vicinity of
the pulmonary hilum (called the zone of the
proximal bronchial tree) was associated with a
markedly higher risk of toxicity.
91. RTOG 0236:
•59 patients
• Median age 72
• All pts inoperable
•T1 – 80%; T2- 20%
•Dose: 60Gy in 3 fxs (BED 180)
Median FU 3 yrs:
•Local control = 97.6%
•Distant mets = 22.1%
•Overall survival @3yrs = 55.8%
•Median survival = 48 months
93. SBRT: LIVER
• Underlying severe liver disease often renders patients
medically inoperable
• Other nonsurgical therapies have generally achieved
at best rather modest success in that setting.
94. Challenges in Targeting Liver Tumors
• Limited visualization of the target
• Liver deformation with respiration
• Changes in GI organ luminal filling
– Critical structures (stomach) may change in shape
and position between planning and treatment
• Interfraction target displacement with respect to bony
anatomy
95. First Liver SBRT Experience
• 50 patients treated to 75 lesions with SBRT for primary and
metastatic liver tumors
• 15 to 45 Gy, 1-5 fractions
• Mean follow-up of 12 months
• 30% of tumors demonstrated growth arrest, 40% were reduced
in size, and 32% disappeared by imaging studies
• 4 local failures (5.3%)
• Mean survival time was 13.4 months
Blomgren, et. al., J Radiosurgery, 1998
96.
97. SBRT:SPINE
SBRT is an emerging technology used for the treatment of
spinal tumors.
• Effective dose escalation
• For patients who are not candidates for conventional
radiotherapy
• To improve the quality of life for patients who may be spared a
prolonged treatment course.
• Acute Radiation toxicity is reduced.
98. Indications for Spinal SBRT
Pain control in vertebral metastases
Malignant Epidural Spinal Cord compression
Benign Spinal Cord Tumors
99. Dose volume constraints
• In a Randomized trail of 260 patients investigators have not
observed a single case of Myelopathy at 1 year with dose of
8Gy *1fr.
• Partial volume tolerance of the human spinal cord to
Radiosurgery was analyzed in 177 patients with 230 metastatic
lesions.
The authors concluded that an acceptable estimate of partial cord
tolerance is 10 Gy to the 10% volume.
1.Rades D, Stalpers LJ, Veninga T et al. J Clin Oncol 23:3366–3375
2.Ryu S, Jin JY, Jin R et al 2007Cancer 109:628–636
100. • The a/b ratio of Prostrate Cancer is lower than for most other
tumors. Values between 1.2 and 3 Gy are suggested.
• It is lower than surrounding normal tissues like rectum (a/b of
4 Gy for late rectal sequelae).
• It is hypothesized that hypofractionation if accurately
delivered increases the tumor control by sparing surrounding
late responding normal tissues.
SBRT:PROSTRATE
101. Indications
Primary treatment for organ confined low risk
prostrate cancer
Dose escalation for intermediate and high risk
prostrate cancer
103. SBRT: PANCREAS
Stereotactic body radiation therapy (SBRT) In Pancreas
is indicated for
1.Boderline resectable tumors to improve resectability
in Neo Adjuvuvant setting.
2.In Unresectable due to their lower life expectancy to
reduce 5 -6 weeks treatment to less than 5 days
3.In resectecd Ca Pancreas with positive margins.
104. Challenges of SBRT in Pancreas
The head of the pancreas, where majority of tumors reside, is
in close proximity to the C-loop of the duodenum
Delivery of conventionally fractionated radiation (1.8–2
Gy/day) to more than 50 Gy results in damage to the small
bowel such as ulcerations, stenosis, bleeding, and perforation.
The pancreas move with respiration, as well as with peristalsis
that is not easily predictable.
105.
106. SIDE EFFECTS
Normal Tissue Toxicity
– Lung: pneumonitis and fibrosis
– Pancreas: duodenum and stomach
– Spine lesions: cord
– Prostate: rectum and bladder
– Liver: normal liver (radiation induced liver disease-
RILD)
