1. RTOG 0813
Seamless Phase I/II Study of Stereotactic Lung Radiotherapy (SBRT) For Early Stage, Centrally Located, Non-Small Cell Lung Cancer (NSCLC) In Medically Inoperable Patients
Seth R. Duffy, BSPH

2. Radiation Therapy Oncology Group (RTOG)
Image Source:
Radiation Therapy Oncology Group (RTOG)
RTOG 0813 saw its inception and activation in February of 2009
Served as one of the forerunners in the emergence of SBRT treatment techniques
SBRT is unique in that it delivers hypofractionated treatments of high-doses
Clinical locations (209) approved through a rigorous approval process by the RTOG headquarters

3. Epidemiology: Lung Cancer
The Leading Cause of Cancer-Related Deaths in the United States and Globally.
Most Common Cancer World-Wide Since (Incidence and Mortality)
5-Year Survival Rate of 15.6%.
Median Age of Diagnosis is 71 Years of Age.
Adenocarcinoma has replaced squamous cell as the most prevalent type of NSCLC (2013).
Citation [5]

4. Inclusion Criteria for Potential Participants
Eligible (Accepted)
Exclusion (Denied)
Pathologically Proven Diagnosis of NSCLC
Staging of T1-2, N0, M0
Non-Small Cell Lung Cancer
Tumor Size ≤ 5cm
Not A Candidate for Surgical Resection
Deemed Medically Inoperable By An Experienced Thoracic Surgeon
Tumor Within The Zone of The Proximal Bronchial Tree
Measurable Disease
Patient Provision of Informed Consent
At Least 9 Forms of Consent
Also Continued Consent Throughout The Trial
Not 18 Years Of Age
Zubrod Performance Status Outside 0-2 Range
4 Weeks Prior to Registration
Excess Pleural Effusion
Pregnant or Positive Serum
Within 72 Hours of Registration
Prior Invasive Malignancy Within The Past 2 Years
Other Than Melanomatous Skin Cancer
Previously Irradiated Region of Study (Causing Overlap)
Excessive Comorbidities
No Concurrent therapy
Including Standard Fractionated RT or Surgery or Systemic Chemotherapy

5. Protocol Objectives In RTOG 0813
What does this clinical trial hope to accomplish?
Phase I Portion:
Phase II Portion:
Secondary Objectives:
Tertiary Objectives:
To determine the maximal tolerated dose (MTD) of SBRT for centrally- located NSCLC and the efficacy of that dose in patients who are not operative candidates. (8/20/10)
To estimate the primary tumor control rate at the MTD of SBRT.
To estimate rates of ≥ grade 3 CTCAE, v. 4 adverse events other than a dose-limiting toxicity (DLT) which is possibly, probably, or definitely related to treatment and which occurs within 1 year from the start of SBRT.
To estimate rates of late adverse events (> 1 year from starting SBRT)
To estimate primary tumor control and progression-free and overall survival rates for patients treated with this regimen.
See Reference Section 2.0 in RTOG 0813

6. escalation in future patients (or dose-limiting) will occur.
Protocol Section 6.1
Stereotactic Dose Fractionation
Patients are to be treated with 5 fractions of radiation, on an every other day basis (2-3 treatments per week with a minimum of 40 hours between treatments).
The [red box] indicates the protocol starting dose, “Level 5”, from which dose
escalation in future patients (or dose-limiting) will occur.

7. Pre-Treatment Planning Preparation
Protocol Section
Technical Factors
Simulation
Localization
-Only X-ray photon beams of energies 4-10 MV -Minimum field dimensions of 3.5 cm is required to account for uncertainties in beam commissioning -Heterogeneity corrections must be utilized when planning with IMRT -Reliable abdominal compression, accelerator beam gating, tumor tracking, and active breath-holding techniques may all be utilized once approved by the PI and Study Co-Chairs
-Achieving the most comfortable, stable patient positioning possible is important
-Stereotactic body frames, with large rigid pillows, may be used
-GTV volume must not deviate beyond the confines of the PTV as defined by the physician
-CT simulation should be the primary imaging modality and should be performed with IV contrast
≤ 3.00 mm scan slice thickness
Helical and 4DCT are both acceptable imaging methods
-Isocenter, or reference point, port localization images must be taken at each treatment on the specific linac to deliver treatment ~AP and Lateral -Verification CT scans and portal films may be taken at the discretion of the institution / physician -The 3-D fixed coordinate system should be defined by reliable fiducial markers. ~Radiopaque markers, rods, or even metallic seeds placed within the tumor itself

8. Dosimetry & Treatment Planning
Protocol Section
Critical Structures
Contouring
3D Conformal
IMRT
Plan Evaluation
Conformality & Dose Tolerance

9. Critical Structures Esophagus Spinal Cord Great Vessels
Spanning between the foramen magnum to the L1-L2 interspace, the spinal cord is one of the most essential structures within the human body. This protocol outlines that this structure be contoured to the bony limits of the spinal canal.
The esophagus is a hollow transporting structure that assists in the digestion of solids and liquids. Measures 25-30cm in
length. This structure is contoured to include the fatty surrounding tissues as well.
Great Vessels
Heart / Pericardium
Five great vessels enter and leave the heart: the superior and inferior vena cava, the pulmonary artery, the pulmonary vein and the aorta. The primary function of which are to circulate blood (oxygenated and deoxygenated).
The human heart is comprised of four chambers: the right atrium and ventricle and the left atrium and ventricle.
The pericardium is a fluid filled sac that
Surrounds the heart and the proximal ends of the aorta, vena cava, and pulmonary artery.

10. The Proximal Bronchial Tree
2cm Margin
The Proximal Bronchial Tree
Defined as: The distal trachea (2cm following the proximal trachea), the carina, and the two major mainstem bronchi, portions of the upper lobe bronchi, the intermedius bronchus, the right middle lobe bronchus, the linguar bronchus, and the right and left lower lobe bronchus.
Although this structure is not extensively evaluated upon dose received, it plays an important role in delineation of who is eligible for this protocol versus who is not eligible.

11. Critical Structures Skin Non-Adjacent Wall Trachea Whole Lung
While often overlooked, the skin is essential to the human body because it not only protects the underlying tissues and organs but also assists in the body’s regulation of temperature as well as giving sensations of touch, hot, and cold.
The Non-Adjacent Wall structure is something specific to this protocol that accounts for dose-spillage past the midline of the body and into the half where the disease does not exist.
Trachea
Whole Lung
Approximately 11.5cm in length and 2.5
cm in diameter. The trachea provides a path for respiration to occur. This function is further assisted (and strengthened) by tracheal cartilages.
The whole lung encompasses both right and left lungs, per protocol request. This also includes collapsed lungs. All GTV must be removed from this structure’s contour. The Lungs are essential to respiration and must be correctly contoured and monitored.

12. Image From: http://www. nlm. nih. gov/medlineplus/ency/imagepages/9129
The Brachial Plexus
The brachial plexus has been described as: A beautiful, intricate, and complex structure that comprises the connections of the spinal nerves to their terminal branches in the upper extremity.”[8]
Clinically divided into five unique zones but not within this protocol
Emerges from the posterior triangle of the neck, bordering the sternocleidomastoid muscle

13. Delineation of Target Volumes
RTOG 0831 Section 6.4 and ICRU-62
GTV
CTV
PTV
Gross Tumor Volume Defined As: The Visible, Palpable, Known Disease Region as Determined by an Experienced Oncologist. Contoured As: Gross Disease
Clinical Target Volume
Defined As: A Tissue Volume
of the GTV and any Suspected Microscopic Disease
Contoured As: GTV+Microscopic
Planning Target Volume
Defined As: The Geometrical Concept that Encompasses the Previous Structures with Treatment Planning in Mind.
Contoured As: GTV (or ITV) + 0.5cm
in the axial plane & 1.0cm in the longitudinal plane
ITV
Internal Target Volume
Defined As: The Expansion of the CTV to account for
internal movement. (ex. Respiration)
Contoured As: GTV+CTV+Motion
ITV
PTV

14. 3D Conformal Treatment Planning
Non-Coplanar Beam Arrangement
Beams Eye
View
3D Conformal Treatment Planning
Section
3-Dimensional beam arrangements, both co-planar and non-coplanar, can be used.
This protocol specifies that 10 or more static, non-opposing, beams should be utilized.
The field size and shape should correspond identically to the PTV within the BEV.
All normalization is done to the center of the PTV and all hotspots must remain inside it.

15. IMRT Treatment Planning
Image From:
IMRT Treatment Planning
Section
IMRT should only be chosen when 3D conformal planning does not adequately address target coverage, OAR dose limits, or dose spillage concerns.
The protocol recommends about two to three segments per beam to avoid complex beam fluence issues.
Dose spillage directly relates to the dose gradients observed at/past the PTV edges.

16. Plan Evaluation
Participant Safety and Wellbeing Remains Constant Throughout This Protocol:
Necessitating Thorough Plan Evaluation
Plan evaluation can be performed by referencing the strict guidelines set forth by the RTOG.
Tables throughout section 6.5 highlight the specific PTV dose coverage needs, the hot spot restrictions, as well as recommendations for dose gradients near organs at risk.
Figure From RTOG 0813 Sect. 6.5

17. Conformality & Dose Tolerance
Section 6.5
Exceeding a max dose point is a protocol violation, however the other doses are suggested limits supported by current (2010) research.
-PTV coverage tables indicate specific tolerable deviations based on PTV size (cc). [Table 1]
Deviation from the specified PTV limits is against protocol standards.
Tables Directly From RTOG Protocol 0813

18. In The End, Who Will Benefit From This Clinical Trial?
Patients
The Field of Radiation Oncology
Participating Institutions

19. Image From: www.themedicalbag.com
Patients
- Patients in RTOG Clinical Protocol 0813 receive SBRT treatments that deliver highly conformal, effective doses of radiation that can contribute to a longer, disease free, life.
- SBRT is still used in 2015 and has contributed to some of the best clinical outcomes in patients with NSCLC, increased 5-year survival and local control improvements. [6]

20. The Field of Radiation Oncology
Image From:
The Field of Radiation Oncology
-Clinical trials contribute the the field of radiation oncology as a whole because they provide detailed information on current treatment options, emerging techniques, as well as in-depth comparisons that are only possible through these types of studies.
-Without clinical trials such as RTOG 0813, the field would not evolve at such a rapid pace, further exemplifying the necessity these trials pose to the field.

21. Participating Institutions
- Every participating institution has gone through a rigorous registration and approval process that not only demonstrates they are capable of carrying out the procedure but also that they are capable of delivering a high-quality procedure consistently.
- This prestige is something that attracts new staff, patients, and potential trial participants to the facility.

22. THANK YOU FOR WATCHING! REFERENCES:
1. Bailey R. Anatomy of the heart: pericardium. About:Biology Accessed June, 2015.
2. Boundless. Anatomy and physiology: great vessels of the heart. June, Accessed June, 2015.
3. Healthline Medical Team. Healthline body maps: esophagus. February, Accessed June, 2015.
4. Nachum N. The university of Texas Medical School E-Textbook for neurosciences - Chapter 3: anatomy of the spinal cord Accessed June, 2015.
5. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epideminology, etiology, and prevention. Clin Chest Med 2013;32:
6. Allibhai Z,Taremi M, Bezjak A, Brade A, et al. The impact of tumor size on outcomes after stereotactic body radiation therapy for medically inoperable early-stage non-small cell lung cancer. Int J Rad Onc, Bio, Phys 2013;87:
7. RTOG 0813: Seamless phase I/II study of stereotactic lung radiotherapy (SBRT) for early stage, centrally location, non-small cell lung cancer (NSCLC) in medically inoperable patients. (Last Update: 6/8/15)
PI: Bezjak A. Princess Margaret Hospital / University of Toronto
8. Chung KC, Yang LJ, Mcgillicuddy JE. Practical management of pediatric and adult brachial plexus palsies. New York, NY: Edinburgh Publishing;2012. ISBN-13: