Igrt for cervical cancer feb 8 2013 920 a cancer ci 2013
02 suh srs hyderabad 2013 (cancer ci 2013) john h. suh
1. Overview of Stereotactic Radiosurgery
for Brain Tumors
John H. Suh, M.D.
Professor and Chairman, Dept. of Radiation Oncology
Associate Director of the Gamma Knife Center
Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center
Taussig Cancer Institute
3. Outline
• Review the history of stereotactic radiosurgery (SRS)
• Discuss the role of SRS for brain metastases
• Review the results of SRS for benign brain tumors
9. Linac Radiosurgery at CCF -- 1989-
1997
• Adapt linear accelerator
• Base plate and floor stand
• Shotgun collimator
• Rotate gantry and table
position to deliver 5 non-
coplanar arcs
• First program in Ohio
Presentation Title l l 9
16. Epidemiology of Brain Metastases
Primary Tumor Relative Prevalence of Brain Metastases*
Colon: 5% Annual U.S. incidence: > 170K
Ratio Mets/Primary: 10:1
Melanoma: 9% All Cancer Patients: 15 - 30%
Autopsy incidence: 10 - 30%
Unknown primary: 11%
Mean age: 60 years
Median survival: 4-6 months
Other known primary: 13%
Breast: 15%
Lung: 48%
*Incidence increasing with better systemic Rx and improved survival
Wen PY, et al. In: DeVita VT Jr, et al (eds). Cancer: Principles & Practice of Oncology. 2001:2656-2670.
17. Factors Used to Assess Therapy
• Number of metastases
• Size of lesion(s)
• Location
• Neurological deficits
• Age / KPS
• Primary tumor / stage
• Extracranial disease
• Patient’s input
18. Brain Metastases: Recursive Partitioning Analysis
Class I Class II Class III
KPS ≥70 KPS ≥70 KPS <70
KPS ≥ 70
Primary: Primary:
Controlled Uncontrolled
and / or
Age: <65 Age: ≥65
and / or
Extracranial Extracranial
metastases: No metastases: Yes
MST 7.1 m MST 4.2 m MST 2.3 m
20% 65% 15%
Gaspar L, et al., Int J Radiat Oncol Biol Phys. 1997;37:745-51
19. Graded Prognostic Assessment (GPA) for brain metastases
Evaluated 1960 patients from five randomized RTOG studies
Develop a less subjective, more quantitative, easier to use
Score Median survival (months)
0 0.5 1.0 3.5-4 11.0
Age >60 50-59 <50 3 6.9
KPS <70 70-80 90-100 1.5-2.5 3.8
Number of CNS >3 2-3 1 0-1 2.6
metastases
Extracranial Present - None
metastases
Sperduto P et al Int J Radiat Oncol Biol Phys 70:510, 2008
20. WBRT-Alternative Fractionation Regimens
Lack of Progress
Randomization MST
Study N (Total Dose/# Fractions) (months)
Harwood et al. (’77) 101 30/10 vs. 10/1 4.0-4.3
Kurtz et al. (’81) 255 30/10 vs. 50/20 3.9-4.2
Borgelt et al. (’81) 138 10/1 vs. 30/10 vs. 4.2-4.8
40/20
Borgelt et al. (’81) 64 12/2 vs. 20/5 2.8-3.0
Chatani et al. (’85) 70 30/10 vs. 50/20 3.0-4.0
Haie-Meder et al. 216 18/3 vs. 36/6 vs. 43/13 4.2-5.3
(’93)
Priestman et al. (’96) 30/10 vs. 12/2 2.5-2.8
Murray et al. (’97) 445 54.4/34 vs. 30/10 4.5
21. Side Effects of WBRT
• Alopecia
• Fatigue
• Skin erythema
• Headache
• Otitis media
• Somnolence syndrome
• Memory loss
• Radiation necrosis
• Leukoencephalopathy
22. Patients Impaired at Presentation
70 Motor
Function Memory N=401
60 Impairment = Z ≥ 1.5
Executive
50 Function
Percentage
40
Fluency
30
Memory
20
10
0 Trail B
Recog
Delay
Recall
Peg D
Peg ND
COWA
Peg D Peg ND Recall Delay Trail B COWA
Recog
Brain met patients have high rates of baseline deficits
Meyers CA, et al. J Clin Oncol. 2004;22:157-165.
23. Favorable Characteristics of Brain Metastases for SRS
• Radiographically distinct on MRI/CT
• Pseudospherical shape
• Displaces normal brain tissue
• Minimal invasion of normal brain
• Size at presentation ≤3 cm
25. Radiosurgery without WBRT
18 16.3 16.2
RS
16
RS/WBRT
14
RTOG
12
Months
10 8.6
7.9
8 7.1
5.5
6 5.1
4.2
4 2.3
2
0
Class I Class II Class III
272 pts RS only upfront 388 RS + WBRT (non-randomized)
(10-institution retrospective study)
Delayed WBRT does not worsen survival
need, PK, Suh JH, et al. Int. J Radiat Oncol Biol Phys. 53:519-526, 2002.
26. RTOG 95-08
R
S Number of
A Arm 1: Whole brain RT to 37.5
Gy/15 fractions/2.5 Gy
T Metastases N
once daily, 5 days/
1. Single
R 2. 2-3 D week followed by
radiosurgery to all (1-3)
A O metastases
T Extent of M
Extracranial disease
I 1. None I
Arm 2: Whole brain RT to 37.5
F 2. Present
Z Gy/15 fractions/2.5 Gy
Y once daily, 5 days/
E week
27. KAPLAN-MEIER SURVIVAL RTOG 9508
Survival
Single Brain Metastasis
100
— RT + SRS MST = 6.5 mo
Percentage alive
80 --- RT Alone MST = 4.9 mo
60 p = 0.047
40
20
0
0 6 12 18 24
Months
Andrews DW et al. Lancet 363:1665-1672, 2004
28. Phase III randomized trial of SRS +/-WBRT
No prior surgery, SRS, or WBRT
No leukemias, lymphomas, germ-cell tumors, SCLC, leptomeningeal disease
RPA class I /II
patients with R
R SRS (15, 18 or 24 Gy)
1-3 lesions A
A
from known
primary N
N
D SRS + WBRT (30 Gy/12 fx)
58 pts D
Stratification by
– RPA class (I or II)
– number of lesions (1 or 2 vs 3)
– “radioresistant” histologies (melanoma or RCC vs other)
? Baseline neurocognitive function and medications (opioids, sedatives)
Primary endpoint: neurocognitive function
– Defined as a decrease in HVLT-R total recall at 4 months by more than 5 points
– Trial was closed early by data monitoring committee
Chang EL et al. Lancet Oncol 2009:10:1037-1044
29. Neurocognitive decline
“A mean posterior probability of [neurocognitive] decline of 52% for the SRS plus
WBRT group and 24% for the SRS only group.” (96% confidence)
Chang EL et al. Lancet Oncol 2009:10:1037-1044
30. Phase III randomized trial of surgery or SRS +/-WBRT
EORTC 22592-26001
RPA class
I /II patients R
with 1-3 brain R Observation
Surgery A
with stable A
systemic dz or SRS N
N WBRT 30 Gy/10 fx
asymptomatic 359 pts
D
D
primary
WHO PS 0-2
Primary endpoint: deterioration to WHO PS > 2
Eligibility: single < 3.5 cm; 2-3 lesions < 2.5 cm
PTV = 1-2 mm margin
Dose 25 Gy to center with minimum dose of 20 Gy.
Kocher M et al. J Clin Oncol 29:134-141, 2010
31. Phase III randomized trial of surgery or SRS +/-WBRT
EORTC 22592-26001
Observation WBRT p value
Median time WHO PS > 2 10 m 9.5 m 0.71
Median overall survival 10.9 m 10.7 m 0.89
2-year relapse at initial site
Surgery 59% 27% 0.001
SRS 31% 19% 0.04
2-year relapse at new sites
Surgery 42% 23% 0.008
SRS 48% 33% 0.023
Kocher M et al. J Clin Oncol 29:134-141, 2010
32. NCCTG N0574(Intergroup)
PE, <2.0 cm 24 Gy
Patients with R QOL, 2 - 2.9 cm 20 Gy F
&
histologically A Related O
confirmed Arm 1:
N A L
extra-cerebral S RS*
primary tumor
D S L
and 1 to 3 brain O E O
S
metastases M S Arm 2: W
detected by I M RS* + WBRT
MRI Z E (30 Gy/12 fx) U
N
E T <2.0 cm 22 Gy
P
S 2 - 2.9 cm 18 Gy
152 pts
33. SRS of the Post-Operative Cavity
• 72 patients treated at Stanford from 1998-2006
• PTV = GTV in 76%
• 1y LC: 79%
GTR vs. STR .52
Histology .49
Number of Fractions .92
Dose .92
BED .92
Conformity Index .04
Volume .29
Based on result, using 2 mm margin on GTV
Soltys S et al. Int J Radiat Oncol Biol Phys 70, 2008
34. N107C
SRS vs. WBRT Resected Brain Mets
Determine if neurocog progression less at 6 months with SRS
Age <60 vs.
>60
S # Brain Mets R
T 1 vs. 2-4 A SRS Surgical Bed + SRS to
Resected R N unresected brain metastases
Extracranial Dz D
Brain A
Met T O
Histology
I Lung vs.
M WBRT* + SRS to unresected+
F Radioresistant I SRS to unresected
Y vs. Others Z metastases
E
Surgical Cavity
<3 vs. > 3 cm *37.5 Gy/15 fx
192 patients
35. Results with SRS for multiple brain metastases
Suh JH, et al. J Stereo Radiosurg SBRT 1:31-40, 2011
38. Introduction: Meningiomas
• Most common primary
intracranial neoplasm
• ~30% of all intracranial
neoplasms
• Estimated prevalence is 97.5 per
100,000
• Most are identified on imaging
alone
• F:M – 2:1 supratentorial
Klaus et al. Neurosurg 57:1088, 2005
Central Brain Tumor Registry 2007
39. Meningioma
EPIDEMIOLOGY
Most Common Brain and CNS Tumors by Age
CBTRUS Statistical Report: NPCR and SEER Data 2004-2006
Age (yrs) Most Common Histology 2nd Most Common Histology
0-4 Embryonal / Medulloblastoma Pilocytic Astrocytoma
5-9 Pilocytic Astrocytoma Malignant Glioma , NOS
10-14 Pilocytic Astrocytoma Neuronal / Glial
15-19 Pituitary Pilocytic Astrocytoma
20-34 Pituitary Meningioma
35-44 Meningioma Pituitary
45-54 Meningioma Glioblastoma
55-64 Meningioma Glioblastoma
65-74 Meningioma Glioblastoma
75-84 Meningioma Glioblastoma
85+ Meningioma Neoplasm, unspecified
CBTRUS Statistical report: primary brain and central nervous system tumors diagnosed in the United States 2004-2006.
http://www.cbtrus.org/2010-NPCR-SEER/CBTRUS-WEBREPORT-Final-3-2-10.pdf. February 2010
Courtesy of L. Rogers
41. Meningioma
Recurrence-Free Survival by Grade (643 pts)
100
5-yr RFS
90
88% Benign, n=464 (72.1%)
80
70
59%
Percent
60
50
Atypical, n=156 (24.3%)
*
40
28%
30
Anaplastic, n=23 (3.6%)
20
p < 0.001
10
0
0 1 2 3 4 5 6 7 8 9 10
Years
Arie Perry et al, Am J Surg Pathol 21:1455-1465, 1997 & Cancer 85:2046-2056, 1999
42. RTOG - 0539 Schema
Phase II Study of IMRT for Intermediate
and High Risk Meningiomas, and Observation
for Low Risk Meningiomas
Group 1 (Low Risk): New Grade 1, GTR or STR
Group 2 (Interm Risk): Recurrent Grade 1, GTR or STR
New Grade 2, GTR
Group 3 (High Risk): Any Grade 3
Recurrent Grade 2
New Grade 2, STR
Primary endpoint: 3 yr PFS
Group 1
Observation
Group 2
Strata 3D-CRT/IMRT 54 Gy / 30
fxs
Group 3
IMRT 60 Gy / 30 fxs
43. Current EORTC 22042-26042 Trial
Adjuvant postoperative high-dose radiotherapy for
atypical and malignant meningioma: a Phase II and
observation study
44.
45. University of Pittsburgh: long term results
• Updated their 18-year experience in a cohort of
972 patients with 1045 intracranial meningiomas
• 70% women
• 645 patients had middle and posterior fossa
tumors
• Median dose 14 Gy
Kondziolka D, et al. Neurosurg 62(1):53-8, 2008
46. University of Pittsburgh: long term results
• Among 75 patients with a minimum follow-up of 10 years,
the local control rates for grade 1 meningiomas or lesions
without histology were 91% and 95%, respectively.
• Local control for WHO II and III were 50% and 17%,
respectively.
• Symptomatic peritumoral edema was 4 months at mean of 8
months.
Kondziolka D, et al. Neurosurg 62(1):53-8, 2008
47. Treatment options for Pituitary Tumors
• Observation
• Microsurgery
• Medical
• Radiosurgery
• Radiation therapy
• Multimodality approach
Depends on symptoms, tumor size
at presentation, involvement of
adjacent structures, and vicinity to
optic apparatus
48. Indications for radiation therapy and radiosurgery
• Primary therapy
• Adjunctive therapy
• Salvage therapy
50. Pituitary adenoma 20 Gy (13 shots- 16, 8 mm with Blocking)
Optic chiasm dose 7.9 Gy
51. Epidemiology of Vestibular Schwannomas
• 2000-3000 new cases of VS
diagnosed per year in the U.S., an
incidence of 1/100,000 per year
• 8-10% of all primary intracranial
tumors
• 80-90% of all cerebellopontine angle
tumors
• Commonly present between 30-50
year of age
• Can be associated with NF-2
• Incidence of occult VS in human
temporal bones: 0.57-0.87%
56. SRS vs FSR: Jefferson Results
•Retrospective study of 125 patients with AN
•69 treated with SRS (12 Gy to the 50% IDL)
•56 treated with FSR (50 Gy/25 fx)
Tumor Preserv Preserv Preserv Tumor Control
Control Trigem Facial Hearing NF2
SRS 98% 95% 98% 33% 80%
FSR 97% 93% 98% 81% 67%
P value 0.6777 0.5893 0.8202 0.0228 0.6615
Dosing recommendation: 46.8 Gy/26 fx
Andrews D, et al., Int J Radiat Oncol Biol Phys 2001; 50:1265-1278
57. SRS vs FSR from Netherlands
•All treatments were linac-based from 1992 to 1999
•129 patients prospectively randomized to SRS vs. FSR
–Dentate: FSR (20 Gy/5 fx and 25 Gy/5 fx)
–Edentate: SRS (10 Gy and 12.5 Gy)
•Mean Tumor Diameter (FSR: 2.5 cm vs. SRS: 2.6 cm)
Local Control Preserved Preserved VII Preserved Vth
Hearing Function Function
FSR 94% 61% 97% 98%
SRS 100% 75% 93% 92%
Meijer et al. Neurosurg 2003; 56(5): 1390-1396
58. SRS versus FSRT for vestibular schwannomas
200 patients treated at Heidelberg and DFKZ
Hearing preserv SRS <13 Gy and FSRT 57.6 Gy/32 fx
<13 Gy FSRT
SRS
>13 Gy
Combs S, et al. Int J Radiat Oncol Biol Phys 76:193-200, 2010
59. Conclusions
• Stereotactic radiosurgery (SRS) is a safe and effective
treatment option for a variety of brain tumors.
• The use of SRS for brain metastases is increasing.
• SRS is an effective treatment option for patients with
brain metastases.
• SRS is an effective and safe treatment option for
patients with benign brain tumors
60. Title of Presentation Arial Regular 22pt
Single line spacing
Up to 3 lines long
Date 20pts
Author Name 20pts
Author Title 20pts
Editor's Notes
The goal of radiation therapy is to maximize tumor control while minimizing complications. This axes of this graph represent Dose on the X-axis and tumor control or complications to normal tissues on the Y-axis. With respect to tumor control, as dose increases, the chance of tumor control increases. Likewise as dose increases, so does the probability of complication (represented by the red curve). Both these curves are sigmoidal in shape. Initially with low doses, there is little cell kill, and hence little tumor control. At a certain dose, the probability of cell kill increases dramatically, and hence high tumor control. However, beyond a certain dose, the curve again flattens so that increases in dose (while still toxic to tumor), does not increase the probability of further cell killing beyond what a lower dose can achieve. The risk of complication follows this same paradigm. Low dose has little chance of causing complication. However, at certain doses, the complication rate climbs sharply. These curves tend to be parallel, and the goal of radiation oncology is to maximize the potential for tumor killing (or tumor control) while minimizing the potential for normal tissue complications. The white vertical dashed line represents this compromise in therapeutic efficacy to achieve maximal tumor control with minimal normal tissue complication.
Ceramide is the central regulator of apoptosis both in the vascular endothelial cells as well tumor cells. Pharmacologic therapy can be targeted to increase the levels of ceramide in the cells in order to increase radiosensitivity (such as VEGF inhibitors).
Emphasize that RPA Class I and II have the same KPS
Neurologic impairment is very common in brain metastasis patients at presentation, before any sort of treatment is initiated. The bars represent seven neurocognitive tests. The first two, PEG-D and PDG-ND stand for pegboard dominant hand and pegboard non-dominant hand. In this test a patient is given a pegboard with different shapes of pins to insert. The test is timed to see how many pins they can put in. At diagnosis, almost 2/3 of patients are impaired in motor function. The next two bars are recall and delayed memory tests; almost 60% of patients are impaired in these memory tests. The last bar is also a memory test, but for recognition. The bar after delayed memory is a test of executive function that looks at trail-making. Patients are given a sheet of paper with random letters and numbers and are asked to connect the letters to the numbers in terms of their order in the alphabet (e.g., connect 1A, B2, C3, etc.). This is called “executive function” as several abilities are required, including reading, fine motor control, and thought processing. COWA stands for controlled oral word association, which tests verbal fluency. For example, a patient will be given the letter “c” and asked to name words that start with that letter. Or they might be given 20 words and be asked to repeat them. The take-home message is that all of these tests show that many patients have neurologic impairment at the time of diagnosis.
Retrospective review of more 500 patients from 10 institutions comparing patients who received whole brain radiation therapy with those who didn’t. Patients were classified into three groups, RTOG/RPA class 1, 2 or 3. In each class there are three bars. The first bar represents patients undergoing radiosurgery only. This is the median survival. The second bar represents patients who received both radiosurgery and whole brain radiotherapy. There is effectively no difference in the combination. The third bar represents patients who received whole brain radiotherapy, only. Both the radiosurgery bars are better than the whole brain radiation bar, alone. The conclusion from this study was that delayed whole brain radiotherapy did not worsen overall survival.
including asymptomatic cases discovered And one autopsy study looking at combined spinal and intracranial meningiomas found that 2.3% of individuals harboured undiagnosed asymptomatic meningiomas (1000X more common than clinically detected) Brain MRI in Vienna in 532 asymptomatic subjects >75 y.o found incidental meningiomas in 1 out of 35 women