Establishing A Stereotactic Body Radiation Therapy
(SBRT) Clinical Program Part II: Clinical and
Radiobiological Considerations
2009 AAPM National Meeting
July 29, 2009 Anaheim California
Disclosures
UVA has a research relationship with Tomotherapy and has been
provided with a subsidized research planning cluster and research
research
software and we have grant funding for clinical translational projects
projects
including a proposal to develop a STAT SBRT program.
I serve on a Helical Tomotherapy Grant Review Committee for
industryindustry-sponsored clinical translational trials
Paul W. Read M.D. Ph.D.
University of Virginia
Department of Radiation Oncology
Educational Objectives
Clinical Questions for developing an SBRT
program
Clinical Trials Process and Design
Review of Current National Lung SBRT
Protocols
Organ Tolerances
Development of the UVA SBRT program as a
PhysicianPhysician-Physics team approach
Developing an SBRT Program ?
Basic Questions to Consider:
What types of patients do you intend to treat (lung, spine, liver,
liver, other) ?
What patient volume do you anticipate ?
How will surgeons be included in your process ?
What equipment do you have and what do you need for simulation,
respiratory motion management, immobilization, and treatment delivery?
delivery?
How will you standardize the contouring of target volumes and OARs and
what dose constraints on OARs will you use ?
How will all essential personnel be trained ?
Will SBRT be paid for by regional third party payers?
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SBRTSBRT-capable Treatment Units
Clinical Trials Process: approval process
In the United States oncology clinical trials are approved for patient
patient enrollment
by at least two independent institutional committees whose main goal is to
ensure that trials are as safe as possible and ethically conducted
conducted in the best
interests of the patients. These committees may have overlap of jurisdiction
and oversight depending on institutioninstitution-specific committee guidelines.
PRC: Peer Review Committee
Institutional committee generally consisting of oncologists and statisticians
whose primary responsibility is to review and determine the scientific
scientific merit,
rationale, and statistical design of proposed investigatorinvestigator-initiated and
industryindustry-sponsored oncology clinical trials.
IRB: Institutional Review Committee
Institutional committee generally consisting of a wide range of health care
professionals whose primary responsibility is to review and oversee
oversee patient
safety and proper informed consent of all oncology clinical trials
trials including
national cooperative trials.
Read PW Stereotactic Body Radiation Therapy:2007 Update. Community Oncology. 2007; 4(10):616-620
Clinical Trials Process: monitoring process
* Clinical trials can take months to get through these committees.
Institutional Clinical Trial Organization
DMSC: Data Monitoring Safety Committee
In the United States onon-going oncology clinical trials are monitored by DMSCs
whose primary responsibility is to determine if the studies are properly
conducted through an audit and analysis process that includes:
1) Adverse Events: defined as any sign or symptom that a patient reports,
which needs to be captured on protocol specific forms and graded as to
severity and assigned an attribution as to whether this was related
related or
unrelated and expected or unexpected.
2) Protocol Violations: defined as nonnon-compliance with the clinical trial
specifications and guidelines and generally characterized as minor
minor and major
violations.
The DMSC can make recommendations to the PRC and IRB to modify
modify the
consent form or suspend or close patient accrual to an oncology clinical trial
based on:
1) toxicity analysis showing a study has reached protocol specified stopping
rule criteria,
2) the discovery of significant unexpected toxicities,
3) repeated protocol violations
PRC
DMSC
approval
monitoring
IRB
2
Simplified Clinical Trial Classification
Phase I: Dose escalation study with dose limiting toxicity criteria that
that
trigger stopping rules to determine the maximally tolerated dose of a
study agent. Generally single arm and nonnon-randomized.
Phase II: Efficacy study powered to determine if an investigational
treatment meets a specified response in a target study population.
population.
Generally single arm and nonnon-randomized, but not always (example
placebo controlled).
Phase III: If the phase II efficacy data meets or exceeds current
standard of care efficacy data a phase III randomized study is performed
performed
to compare the study treatment with the standard of care treatment
treatment to
determine which is superior.
Depending on the required follow up period for endpoint determination this
process can span well over a decade.
Lung SBRT as a Model for SBRT
Clinical Translational Research
Clear Rationale for SBRT development from failure of
conventionally fractionated dose escalation studies
Curative treatment of early primary lung cancers
Tumor motion incorporated into treatment planning
and/or delivery
Existing Phase I and II national cooperative group trials
To date no phase III randomized SBRT national cooperative trials have been
opened.
Surgical Outcomes for Operable Early NonNonsmall Cell Lung Cancer
Surgical resection with lobectomy,
lobectomy, the best
surgical procedure, results in local control rates
of 90%.
However, patients whose lung function is too
poor to undergo lobectomy were offered a
wedge resection which resulted in reported local
control rates of 5050-85%.
Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 nonsmall cell lung cancer. Ann Thorac Surg 1995;60:615–623.
Nakamura HMP, Kazuyuki S, Kawasaki NM, et al. History of limited resection for non-small cell lung
cancer. Ann Thorac Cardiovasc Surg 2005;11:356–362.
Historical Early NonNon-small Cell Lung Cancer Radiation
Therapy Outcomes for Inoperable Patients
Patients with medically inoperable T1T1-T2N0 lung cancer treated with
conventionally fractionated radiation therapy to 6060-70 Gy had
historical reported local control rates of 3030-50%.
MSKCC and University of Michigan initiated institutional phase I
conventionally fractionated 3D dose escalation studies to 84 and
102.9 Gy respectively to improve local control.
These studies were followed by RTOG 9311, a multimulti-institutional
phase I/II dose escalation study for inoperable lung cancer patients
patients
treated with radiation alone or following induction chemotherapy
with a maximum permissible dose of 83.8 Gy while keeping the total
volume of lung receiving 20 Gy < 25%.
Despite dose escalation, the 2loco-regional control rate for
2-year locothe group that received 83.8 Gy was only 55%.
Rosenzweig K, Fox L, Yorke E, et al. Results of a phase I dose escalation study using threedimensional conformal radiotherapy in the treatment of inoperable non-small cell lung
carcinoma. Cancer 2005;103:2118–2127.
Hayman J, Martel M, Ten Haken R. Dose escalation in non-small cell lung cancer using
three-dimensional conformal radiation therapy: update of a phase I trial. J Clin Oncol
2001;19:127–136.
Bradley J, Graham M, Winter K, et al. Toxicity and outcome results of RTOG 9311: a phase I-II dose escalation study
using three-dimensional conformal radiotherapy in patients with inoperable non-small cell lung cancer. Int J Radiat Oncol
Biol Phys 2005;61:318–328.
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Why did these studies fail to significantly
improve local control for these patients?
In separate reported analysis, Mehta and
Machtay,
Machtay, reported that prolongation of the
treatment time in lung cancer resulted in poorer
survival. With prolongation beyond 55-6 weeks
patients lose 11-2% survival per day thought to
be secondary to clonagen repopulation.
Mehta M, Scrimger R, Mackie R, et al. A new approach to dose escalation in non-small-cell lung
cancer. Int J Radiat Oncol Biol Phys 2001;49:23–33.
Machtay M, Hsu C, Komaki R, et al. Effect of overall treatment time on outcomes after
concurrent chemoradiation or locally advanced nonsmall-cell lung carcinoma: analysis of the
Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys
2005;63:667–671.
Dose Response Curve
Phase I dose escalation early NSCL SBRT trial:
University of Indiana
47 patients were stratified into 3 groups based on tumor size (<3
(<3
cm, 33-5 cm, 55-7 cm).
Dose escalation in cohorts of 3 patients with all patients receiving
receiving 3
fractions of 3D conformal radiation and starting at 8 Gy per fraction.
The maximal tolerated dose was not reached for the 2 smaller
tumor subgroups despite treating to 6060-66 Gy and was 66 Gy for
the largest tumor subgroup.
The reported 22-year local control rate for patients treated with 181824 Gy x 3 fractions was 90%.
Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic
radioablation: results of a phase I study in medically inoperable stage I nonsmall cell lung cancer. Chest 2003;124:1946–1955.
Phase II early NSCL SBRT trial:
University of Indiana
70 patients: stratified for size with patients with smaller tumors,
tumors, 5
cm or less treated with 60 Gy/
Gy/ 3 fractions and larger tumors treated
with 66 Gy/3 fractions (n=35 for each stratification).
The actuarial 22-year local control rate was 95% with a 56% overall
survival with death mostly from coco-morbid illness.
Dose limiting toxicity (grade 33-5) was reported to be 11 times
greater for patients treated with central tumors compared to
peripheral tumors.
Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic
radioablation: results of a phase I study in medically inoperable stage
I non-small cell lung cancer. Chest 2003;124:1946–1955.
Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating
central tumors in a phase II study of stereotactic body radiation therapy for
medically inoperable early-stage lung cancer. J Clin Oncol 2006;24:4833–4839.
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Summary of Three Recent/Current
RTOG Lung SBRT Trials
RTOG 0236 phase II closed n = 52
RTOG 0618 phase II
open
n = 33
RTOG 0813 phase I/II open
n = 94
RTOG 0236
A Phase II Trial of Stereotactic Body Radiation
Therapy (SBRT) in the Treatment of Patients with
Medically Inoperable Stage I/II NonNon-Small Cell
Lung Cancer
Patients with T1, T2 (G
(G 5 cm), T3 (G
(G 5 cm), N0, M0 medically
inoperable nonnon-small cell lung cancer; patients with T3 tumors chest
wall primary tumors only; no patients with tumors of any TT-stage in
the zone of the proximal bronchial tree.
Treatment: Stereotactic Body Radiation Therapy (SBRT), 20 Gy per
fraction for 3 fractions over 1½
Gy.
1½-2 weeks, for a total of 60 Gy.
MultiMulti-institutional national trial to determine if the excellent
institutional phase II trial local control data could be reproduced
reproduced in a
multimulti-institutional trial setting.
RTOG 0618
A Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) in
the Treatment of Patients with Operable Stage I/II NonNon-Small Cell
Lung Cancer
Patients with T1, T2 (G
(G 5 cm), T3 (G
(G 5 cm), N0, M0 medically inoperable nonnon-small
cell lung cancer; patients with T3 tumors chest wall primary tumors
tumors only; no patients
with tumors of any TT-stage in the zone of the proximal bronchial tree.
Treatment: Stereotactic Body Radiation Therapy (SBRT), 20 Gy per fraction for 3
fractions over 1½
1½-2 weeks, for a total of 60 Gy
Same eligibility and treatment as RTOG 0236 except for operable patients and postpostradiation adjuvant chemotherapy is recommended for patients with T2 tumors > 4
cm and all T3 tumors.
RTOG 0813
PHASE I/II STUDY OF STEREOTACTIC LUNG RADIOTHERAPY
(SBRT)FOR EARLY STAGE, CENTRALLY LOCATED, NONNON-SMALL
CELL LUNG CANCER (NSCLC) IN MEDICALLY INOPERABLE
PATIENTS
Patients with stage T1T1-2N0M0, nonnon-small cell lung cancer, tumor size G 5
cm, who are not candidates for a complete surgical resection in the
opinion of a thoracic surgeon; only patients with tumors within or
touching the zone of the proximal bronchial tree or adjacent to
mediastinal or pericardial pleura
This study will determine the maximally tolerated dose and efficacy
efficacy of
SBRT for centrally located tumors.
This trial would potentially provide preliminary data for a phase
phase III trial comparing
surgical resection vs. lung SBRT.
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Japanese Lung SBRT experience
Uematsu reported a 94% 33-year local control
rate for patients treated with 5050-60 Gy in 55-6
fractions.
Nagata reported a 98% local control rate at 30
months for patients treated with 48 Gy in 4
fractions.
Onishi reported a retrospective study involving
245 patients treated at 13 institutions with a
92% 22-year median local control rate for
patients treated to a biologic effective dose of at
least 100 Gy.
Gy.
•Uematsu M, Shioda A, Tahara K, et al. Computed tomography-guided frameless stereotactic radiotherapy for stage I nonsmall cell lung cancer: 5-year experience. Int J Radiat Oncol Biol Phys 2001;51:666–670.
•Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 4 Gy of
stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body
frame. Int J Radiat Oncol Biol Phys 2005;63:1427–1431.
JCOG 0403
Single arm phase II study for patients with
stage 1A lung cancer
Primary endpoint is 33-year overall survival
Study will stratify patients based on
medically operable (n=65) and medically
inoperable (n=100)
Treatment is 48 Gy/
Gy/ 4 fractions prescribed
to the isocenter.
isocenter.
•Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung
carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 2004;101:1623–1631
OAR Dose Tolerances for
RTOG 0236 and 0618
Summary of reported local control rates for
early lung cancer patients treated with SBRT
(80(80-95%)
Timmerman RD, Park C, Kavanaugh BD. The North American Experience
with Stereotactic Body Radiation Therapy in Non-Small Cell Lung Cancer. J
Thorac Oncol. 2007;2:suppl 3. S101-S112.
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Timmerman’
Timmerman’s Lung SBRT Conclusions
Literature Review of SBRT
Related Chest Wall Toxicity
1. The maximal tolerated dose for peripheral primary tumors less than 7 cm is 60 to 66 Gy in
three fractions.
2. The maximal tolerated dose for centrally located primary tumors less than 7 cm is unknown
but is exceeded by doses of 60 to 66 Gy in three fractions.
Chest
Wall
Pain
Rib
Fracture
17%
6%
3-5
N/A
3%
30 Gy
1
N/A
5%
4848-60 Gy
3-5
23%
14%
Number
Patients
Dose
Fractionatio
n
Norihisa
et al.
34
4848-60 Gy
3-5
5. Despite clinical staging, isolated hilar and mediastinal nodal failures occur in less than 5% of
patients after SBRT.
Zimmermann
et al.
68
37.5 Gy
6. Despite staging with whole body PET scans, approximately 20% of patients develop distant
metastatic disease.
Fritz et al.
40
Princess
Margret
76
3. A prescription dose less than 54 Gy in three fractions is associated with maximal local control
of approximately 70% to 80% for patients treated in prospective trials with adequate follow-up in
North America and Europe.
4. A prescription dose of 54 Gy or more in three fractions has been demonstrated to achieve
local control in more than 90% of treated tumors in prospective testing.
7. Although it is well-known that toxicity after large dose per fraction treatment occurs late, it is
also recognized that tumor recurrence likewise occurs late after treatment with the median time
to recurrence of 16 to 24 months after therapy.
8. Despite excellent local control after SBRT, patient survival for medically inoperable early-stage
lung cancer is very poor, mainly due to severe and lifethreatening coexisting morbidities and the
eventual appearance of metastatic disease.
Unexpected Lung Toxicity:
UVA Patient with IPF treated with lung SBRT
Study
Unexpected Lung Toxicity:
severe radiation pneumonitis in a patient
with IPF treated with lung SBRT
Takeda A, Enomoto T, Sanuki N, Nakajima T, Takeda T, Sayama K, Kunieda E.
Acute exacerbation of subclinical idiopathic pulmonary fibrosis triggered by hypofractionated stereotactic
body radiotherapy in a patient with primary lung cancer and slightly focal honeycombing. Radiat
Med.2008;26(8):504-7.
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How do we account for organ function in our dose tolerance
constraints ?
Are DVH and maximum point doses constraints adequate ?
Lung Motion Determination Using Dynamic MRI:
Pilot Study to test the reproducibility of breathing
J. Cai, K. Sheng, T.A. Altes, J. Molly, P. Read, J. Brookeman* (2007)
Evaluation of the reproducibility of lung motion probability distribution function
(PDF) using dynamic MRI. Phys. Med. Biol. 52:365-373.
Results: 3D Displacement with
hyperpolarized gas grid tagging
Additional Excellent References to aid in
starting an SBRT program
Liver SBRT Phase I/II Trials
Schefter TE, Kavanagh BD, Timmerman RD, et al. A phase I trial of stereotactic body radiation
therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys 2005;62:1371–1378.
Hoyer M, Roed H, Traberg Hansen A, et al. Phase II study on stereotactic body radiotherapy of
colorectal metastases. Acta Oncol 2006;45:823–830.
Normal Organ Tolerances for 1,3,5 fraction SBRT from
Univ. of Texas Southwestern
Timmerman RD. An Overview of Hypofractionation and Introduction to This Issue of Seminars in
Radiation Oncology. 2008;18(4):2152008;18(4):215-222.
Spinal Radiosurgery
Given lung motion we really don’
don’t have an accurately
determined lung DVH
Sahgul A, Larson DA, Chang EL. Stereotactic Body Radiosurgery for Spinal Metastases: A Critical
Review. Int. J. Radiat.
71(3):652-665.
Oncol. Biol. Phys. 2008; 71(3):652Radiat. Oncol.
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UVA SBRT Development
Developed as a clinical translational research program
with close physicianphysician-physicist collaboration with
institutional grant funding
Goal was to build a Helical TomoTherapyTomoTherapy-based SBRT
program as our other 2 linacs were over 10 years old.
We acquired the 12th clinical Helical TomoTherapy Unit
We had a single slice CT simulator and a fluoroscopic
simulator.
Basic Dosimetric feasibility studies began in 2004
First patient was treated in 2/2005
Lung Phantom SBRT Dosimetry
Motion Phantom to determine how motion
effects the dose distribution
Designed by Ke Sheng,
Sheng, Ph.D. and fabricated at UVA
Programmable step motor allows for computer driven lung motion
profiles
Effect of Respiratory Amplitude and
Periodicity on PTV Coverage
Brian Kanajaki, James Larner, Janelle Molloy, Paul Read, Ke Sheng*
(2007) A motion phantom study on helical tomotherapy: the dosimetric
impacts of delivery technique and motion Phys. Med. Biol.52:365-373.
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Dosimetric study to determine the HT
maximal permissible lung SBRT PTV dose
Maximal permissible dose to meet RTOG
0236 Criteria: V20 Gy to < 10% lung
Dosimetric Criteria of RTOG 0236
Lung Volume (cc)
Heart, Trachea, Ipsilateral Bronchus: max pt dose 30Gy
Esophagus: max pt dose 27 Gy
Brachial Plexus: max pt dose 24 Gy
Spinal Cord: max point dose 18 Gy
No deviation V20 Gy less than 10% of lung
Minor deviation V20 Gy less than 15% of lung
Different Lung Volumes used
Volumes of 20002000-5000 cc used
GTVs from 11-6 cm with 5 mm radial and 1 cm
craniocaudad expansions for the PTV
2000
GTV size (cm)
2500
3000
PTV vol (cc)
3500
4000
4500
5000
Dose (Gy
(Gy))
2
28
60
3
60
57
60
4
110
48
48
51
60
60
60
5
195
39
39
42
45
51
57
60
6
296
33
36
39
42
42
42
45
60
Regression analysis and equations to determine the maximal
permissible HT lung SBRT PTV dose for initial treatment
planning
Maximal permissible dose to meet RTOG
0236 Criteria: V20 Gy to < 15% lung
Lung Volume (cc)
2000
2500
3000
GTV size (cm)
PTV vol (cc)
4
110
60
60
60
5
195
51
54
57
6
296
48
51
54
3500
4000
4500
5000
60
60
60
60
57
57
57
57
Dose (Gy
(Gy))
Dose = 0.0056 (Lung vol) - 0.094 (PTV) + 48
Baisden JM, Romney DA, Reish AG, Sheng K, Jones D, Read PW, Larner JM. (2007)
Dose as a Function of Lung Volume and PTV in Helical Tomotherapy-based
Stereotactic Body Radiation Therapy for Small Lung Tumors (accepted with revisions
Int. J. of Radiat. Oncol. Biol. Phys)
For V20 < 10% of lung
Dose = 0.0025 (Lung vol) - 0.034 (PTV) + 56
For V20 < 15% of lung
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Regression analysis and equations to determine
the maximal permissible HT liver SBRT PTV dose
Dynamic MRI and dynamic MRI data rebinned and
resorted as a 4DCT simulation
Dynamic MRI
Joseph Baisden, Ke Sheng, Janelle Molloy, Brian Kavanaugh, James Larner, Paul Read* (2006)
Dose as a Function of Liver Volume and PTV in Helical Tomotherapy IMRT-based Stereotactic
Radiotherapy for Hepatic Metastasis. Int. J. of Radiat. Oncol. Biol. Phys. 66(2):620-625.
Correlation between the respiratory variability and the error in
tumor ITA (ITV) determined from the simulated 4DCT
Rebinned Dynamic MRI as a
4D CT simulation
Real Time Adaptive SBRT treatment
planning and delivery
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TomoHelical
StatRT
Proposed New Work Flow and Patient Care
STAT SBRT and LinacLinac-based SBRT
Patient Consultation
Patient Consultation
Preauthorization
Preauthorization
CT simulation
PACS (pre-contouring)
PACS
(contouring)
Treatment Planning
STAT RT
Real time planning,
delivery, and QA
Physics QA
Treatment Delivery
Representative isodose plans for treating a 23 cc liver
lesion PTV with TomoHelical and StatRT.
Existing Work Flow
Proposed Work Flow
Dose volume histogram (DVH) comparison
between STAT RT and TomoHelical for a SBRT of
a typical liver lesion (3 iterations)
110
StatRT
PTV STAT RT
PTV Tomo
Esophagus STAT RT
Esophagus Tomo
Liver STAT RT
Liver Tomo
Spinal cord STAT RT
Spinal cord Tomo
Lung STAT RT
Lung Tomo
100
90
80
Volume (%)
TomoHelical
70
60
50
40
30
20
10
0
0
2
4
6
8
10 12 14 16 18 20 22
Dose (Gy)
Representative isodose plans for treating a 23 cc lung lesion
PTV with TomoHelical and StatRT.
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Dose volume histogram (DVH) comparison
between STAT RT and TomoHelical for SBRT
of a peripheral lung lesion (3 iterations)
Volume (%)
80
70
60
120
120
100
PTV Beamlet
PTV Full Scatter
Cord Beamlet
Cord-Full Scatter
Esophagus Beamlet
Esophagus Full Scatter
60
40
100
80
Esophagus Beamlet
0
0
5
10
15
20
3 Iterations
25
Cord Beamlet
Cord Full Scatter
Esophagus Full Scatter
40
20
0
PTV Beamlet
PTV Full Scatter
60
20
Dose (Gy)
50
120
100
80
Percen t Volum e
90
P ercent Volume
PTV STAT RT
PTV Tomo
Esophagus STAT RT
Esophagus Tomo
Spinal cord STAT RT
Spinal cord Tomo
Heart STAT RT
Heart Tomo
Total lung STAT RT
Total lung Tomo
Chest wall STAT RT
Chest wall Tomo
100
Percent Volume
110
Dose volume histogram (DVH) comparison
between STAT RT and TomoHelical for SBRT
of a spinal metastasis (1,3,7 iterations)
80
PTV Beamlet
PTV Full Scatter
Cord Beamlet
60
Cord Full Scatter
Esophagus Beamlet
Esophagus Full Scatter
40
20
0
0
5
10
15
20
Dose (Gy)
5 Iterations
25
0
5
10
15
20
25
Dose (Gy)
7 Iterations
40
30
20
10
0
0
2
4
6
8
10 12 14 16 18 20 22
Dose (Gy)
Special Thanks
Dr. Ke Sheng PhD
Dr. James Larner MD
Dr. Stanley Benedict PhD
Dr. Jing Cai,
Cai, PhD
Dr. Alyson McIntosh, MD
Dr. Neal Dunlap, MD
Dr. Asal Shoushtari,
Shoushtari, MD
Dr. Brian Kavanaugh
Tomotherapy Collaborators
UVA Cancer Center
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