A Trial Introduction to NRG-BR001: A Phase 1 Study of SBRT ... Credentialing Materials/NRG... · A Trial Introduction to NRG-BR001: A Phase 1 Study of SBRT for the Treatment of Multiple

A Trial Introduction to NRG-BR001: A Phase 1 Study of SBRT for the

Treatment of Multiple Metastases Steven Chmura, M.D., Ph.D.

Principal Investigator

The University of Chicago

NRG BR001: Talk Outline

1. Hypothesis & trial design

2. Rationale for physics & credentialing requirements

3. Credentialing requirements

4. Technical requirements

5. Benchmark planning & credentialing review

6. IGRT credentialing review

7. Available resources & guidelines

Hypothesis & Trial Design

Study Rationale

• Metastatic spread of disease is the leading cause of cancer related death.

• Oligometastases—the clinical scenario where a patient presents with distant relapse with a limited number of metastases—has been identified.

• Preliminary studies suggest aggressive treatment of metastases may be warranted in addition to effective systemic management – Prevent further progression of metastatic disease or possibly improve

survival duration. •

Are patients with limited metastasis being treated with SBRT?

http://tinyurl.com/oligomets

http://tinyurl.com/oligomets

International Survey of SBRT use for Oligometastases:

• >1000 respondents – 43 countries

– >8000 distributed

• 61% use SBRT to treat < 3 metastases – Most common reasons for use:

• Demonstration of durable local control

• For research purposes

– Most common reasons NOT used: • Lack of convincing data

Study Rationale cont. • Reports detailing the safety and tolerability of treating

multiple and/or overlapping metastases are scarce.

• Limited information about SBRT toxicity and safety when metastases are in close proximity (i.e., less than 5 cm) – Patients with only two metastases: must be within 5 cm of each other

• Treatment of > 2 metastatic sites with SBRT has not been studied in the multi institutional setting – Patients with three or to four lesions: proximity is not a factor in

determining eligibility.

Primary Objectives

To determine the recommended SBRT dose for each of the metastatic locations being treated given the individual and overlapping fields when multiple metastases are treated with SBRT in a national clinical trials network setting

Secondary Objectives

1. To estimate rates of ≥ grade 3 adverse events which are possibly, probably, or definitely related to treatment and which occurs within 6 months from the start of SBRT to multiple metastases

2. To estimate the rates of long-term adverse events occurring up to 2 years from the end of SBRT

3. To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout radiation therapy processes

Study Schema

Patients with metastatic breast, adenocarcinoma of the prostate or non-small cell lung cancer with ≤ 4

metastases; all metastases not resected must be amenable to SBRT

REGISTER

SBRT (in 3 or 5 fractions) to all existing metastases in 1-3 weeks

NRG BR001: Hypothesis & Trial Design

• Eligibility (SECTION 3.1):

• 2 metastases within 5 cm of each other OR

• 3-4 metastases

• Exclusion (SECTION 3.2):

• Brain metastases

• Active disease at primary site

• Prior palliative RT to metastases

• Metastases within 3 cm of previously irradiated structures (cord, bowel, lung, brachial plexus)


• Each metastasis is assigned to one of seven anatomic locations:

• Lung peripheral

• Lung central

• Mediastinal/cervical lymph node

• Liver

• Spinal/Para-spinal (i.e., within 1cm of vertebral body)

• Osseous (excluding femoral head)

• Abdominal-pelvic (e.g., lymph node/adrenal)


Dose De-escalation Only

Table 6-1


• Six patients are assigned to each metastatic location:

• All 6 are observed for 6 months

• If 0-1 DLT then recommended dose reached

• >2 DLT then dose de-escalated

• If De-escalated:

• Accrue an additional 6 patients

• If 0-1 DLT then recommended dose reached

• >2 DLT then no recommended dose

Benchmark & FAQ for NRG-BR001: A Phase 1 Study of SBRT for the

Treatment of Multiple Metastases Hania Al-Hallaq, Ph.D.

Medical Physics Co-Chair


NRG BR001: Talk Outline

1. Hypothesis & trial design

2. Rationale for physics & credentialing requirements

3. Credentialing requirements

4. Technical requirements

5. Benchmark planning & credentialing review

6. IGRT credentialing review

7. Available resources & guidelines

Rationale for Physics & Credentialing Requirements

NRG BR001: Rationale for Physics Requirements

• How to reconcile challenges encountered when treating multiple anatomical sites?

– Motion management

– IGRT

– Composite dose

– Organ-at-risk (OAR) constraints for lesions potentially treated on separate days

– Positioning accuracy of multiple lesions treated on separate days

NRG BR001: Multiple Metastases

Metastatic Locations Initial Starting Dose

Lung--Peripheral 45 Gy

(3 fractions)

Lung—Central 50 Gy

(5 fractions)

Mediastinal/Cervical Lymph Node 50 Gy

(5 fractions)

Liver 45 Gy

(3 fractions)

Spinal/Paraspinal 30 Gy

(3 fractions)

Osseous 30 Gy

(3 fractions)

Abdominal-pelvic metastases

(lymph node/adrenal gland)

45 Gy

(3 fractions)

NRG BR001: Rationale for Physics Requirements

• How to be flexible to include the following?

– Various dose fractionation regimens • 45Gy in 3 fractions, 50Gy in 5 fractions

– Various treatment systems • CyberKnife, Linac, Vero, Tomotherapy

– Various motion management techniques • Abdominal compression, respiratory gating, free-breathing

– Secondary imaging modalities utilized for GTV delineation • MRI, PET

NRG BR001: Rationale for Credentialing Requirements

• How to be lenient enough to credential for 7 anatomical sites without the burden of credentialing for each site?

• Credentialing tied to function being tested:

– Single versus multiple isocenter

– With or without motion management

– IGRT for lesions in soft-tissue versus bony anatomy

Credentialing Requirements (SECTION 5)

3DCRT

credentialing SBRT

credentialing

Separate isocenter

for each metastasis

Phantom irradiation with

motion management:

Lung/Spine targets with

SBRT using beams sharing a

single isocenter

Benchmark

planning

IMRT

credentialing

Facility

Questionnaire

Phantom

irradiation with

step-and-shoot

or dynamic

delivery

Phantom

irradiation

with 3D

conformal

delivery

Single isocenter

for multiple

metastases

Phantom irradiation with

motion management:

Lung target with SBRT

IGRT

credentialing

Lung or

Liver SBRT

case treated

with motion

management

Spine

SBRT

case

Benchmark Planning

• Planning tool by which to familiarize each institution with the specific planning goals of the protocol

• Pre-enrollment review versus pre-treatment review

NRG BR001: IROC Phantoms

• Institutions need to credential for only the most complex modality they intend to use! (3D IMRT VMAT)

• The following techniques must be included in credentialing prior to use in patients enrolled onto BR001: – Motion management technique

– FFF beams

• Techniques may be combined – Ex: IMRT using FFF delivered with motion management

NRG BR001: IROC SBRT Phantoms

Lung & Spine Irradiation Lung

NRG BR001: IGRT Credentialing

• Data from 2 anatomical sites:

– Lung/Liver with same motion management technique your institution will utilize for BR001

– Spine

Insert screenshots of Duke credentialing

Technical Requirements

NRG BR001: Technical requirements

• CT simulation: – ≤3mm resolution

– I.V. contrast required for liver lesions

– 4DCT/fluoroscopy required to assess motion

– Motion > 1cm should be corrected (gating, compression, ABC, BH)

• Treatment modality: – Photons only (≥6MV; > 10MV limited for depths > 10cm of non-lung)

– Either IMRT or 3DCRT (≥ 3cm aperture for 3DCRT)

– Separate treatment isocenters for lesions > 10cm apart

• Dose calculations: – Must be corrected for heterogeneities

– Must include composite dose maps

Consensus on Minimum IGRT requirements for SBRT (First protocol to provide consensus data)

Table 6-3: GTV/CTV/PTV Definitions Metastatic Location

Planning

Parameter

Lung

Central

Lung

Peripheral

Liver Abdominal

-pelvic

Mediastinal

/

Cervical

Lymph

Nodes

Osseous Spinal

CT window/level Pulmonary/

mediastinal

Pulmonary/

mediastinal

Hepatic Soft tissue Pulmonary/

mediastinal

Bone/soft

tissue

Bone/soft

tissue

Additional Studies PET/CT PET/CT PET/CT

MRI

PET/CT

MRI

PET/CT PET/CT

MRI

PET/CT

MRI

Multiphase CT N/A N/A N/A Yes N/A N/A N/A

Anatomy of focus

for multi-

modality fusion

Bony

Anatomy

Bony

Anatomy

Liver Bony

anatomy

Bony

anatomy

Bony

anatomy

Bony

anatomy

GTV definition metastasis metastasis metastasis metastasis metastasis metastasis metastasis

CTV definition = GTV/ITV* = GTV/ITV* = GTV/ITV* =GTV/ITV* = GTV/ITV*+ = GTV = GTV

PTV axial

expansion

= CTV +

5mm**

= CTV +

5mm**

= CTV +

5mm**

= CTV +

5mm**

= CTV +

5mm**

= CTV +

5mm**

= PTV in

RTOG 0631**

(see Figure 6-

2)

PTV craniocaudal

expansion

= CTV +

7mm**

= CTV +

7mm**

= CTV +

7mm**

= CTV +

7mm**

= CTV +

7mm**

= CTV +

7mm**

= PTV in

RTOG 0631**

(see Figure 6-

2)

NRG BR001: Treatment planning guidelines

• 3DCRT: – 7-13 static beams with zero-margin block-to-PTV margin

– Rx isodose line = 60-90% (generally 80-90%)

• VMAT: – Dynamic conformal arcs (>340o)

• 3DCRT/IMRT/VMAT: – Hot spots within target (*)

– Rx isodose volume/PTV volume = 1.2-1.5

– 50% isodose per Table 6-4

– Dose at 2cm from PTV per Table 6-4

* = indicates required planning goals

NRG BR001: Dose Conformality for Single Target per RTOG 0813

NRG BR001: Planning Priorities

• 6.4.4 Planning Priorities

• Every attempt should be made to successfully satisfy all of the planning goals and OAR criteria

without deviation. In some circumstances, it may not be possible to meet all the ideal criteria

leading to plans with an acceptable deviation. Thus, suggested priority of planning goals in

order of importance is:

1. Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose

constraints.

2. Meet dose “compactness” constraints including the prescription isodose surface

coverage, high dose spillage (location and volume), and intermediate dose spillage

(D2cm, and R50%) as these define the “essence” of SBRT. Dose compactness should

be assessed for plans based on treatment dose for a single lesion at a time.

3. Meet critical structure constraints other than those listed in 1. The OAR constraints are

last in priority (except for nervous system tolerance), because they are the least

validated. The “essence” of a stereotactic plan is captured mostly in the dose

compactness criteria, thereby justifying their higher priority. As an example in a case

where not all goals can be met, it would be suggested to meet dose compactness

goals without deviation even at the expense of a non-spinal cord normal tissue having

acceptable deviation. Unacceptable deviations should be avoided in all cases.

4. In cases where PTV coverage cannot be achieved while avoiding unacceptable

deviations to OAR, coverage of a section of PTV including or immediately adjacent to

the OAR may be as low as 70% of the prescription dose ONLY in this situation (see

Section 6.5.4).

NRG BR001: OAR constraints

NRG BR001: Compliance Criteria

Benchmark Planning

BR001 Benchmark Case: Bilateral Adrenal Metastases

LT GTV & PTV RT GTV & PTV:

Overlap with liver

Metastases Overlap with Parallel Organs


LT GTV & PTV:

Overlap with Kidney RT GTV & PTV

Metastases Overlap with Parallel Organs


LT GTV & PTV:

Overlap with Stomach

Metastasis Overlap with Serial Organ

NRG BR001: FAQ

NRG BR001: FAQ

• Can my institution plan the benchmark with a single isocenter even though my institution has not yet credentialed to deliver treatment to 2 metastases using a single isocenter?

– Yes

• What should I do if an OAR is not in the structure set?

– Contour it if you would like to use it for planning

• What QA measurements are required?

– None

• Should the benchmark plan be reviewed by our physician?

– Absolutely! To ensure it’s clinically acceptable

NRG BR001: FAQ

• If the plan is intended to treat both lesions simultaneously on the same day, am I required to submit separate dose grids for each lesion?

– No (e.g., single VMAT plan)

• For an IMRT/VMATplan, is a normalization of 60-90% required?

– No, but ensure conformality is high

• How should the conformality of the plan be assessed?

– See Table 6-4

– 80% isodose should break up between 2 lesions

NRG BR001: FAQ

• I cannot meet the PTV coverage requirements while also meeting all the OAR constraints in Table 6-6. How should these competing constraints be balanced? – BR001 provides guidance on the “planning priorities” (SECTION 6.4.5):

1. Spinal dose constraints, as assessed on the composite dose map, must always be met.

2. PTV coverage may not fall below 70% of the 45 Gy prescription dose in regions overlapping with OAR.

3. No dose >47.25Gy may exist outside PTV. In addition, no dose >47.25Gy may exist in PTV volumes that overlap directly with OAR (e.g., Liver, Kidney_L, Stomach, Bowel). See SECTIONS 6.4.3 & 6.5.4.

– It is left to the discretion of the institution as to whether they will prioritize PTV coverage over OAR (e.g., stomach) constraints.

NRG BR001: Benchmark Evaluation

• How will the benchmark be evaluated? – Dose Volume Analysis (DVA) will be used to tabulate data

– Composite dose will be used to evaluate all OAR constraints including 105% hotspot location

– If each metastasis is planned for treatment on separate days, individual dose maps will be evaluated for PTV coverage

NRG BR001: Dose Volume Analysis (DVA) for Benchmark Evaluation

Benchmark Examples & Reviews

NRG BR001: Benchmark Case 10

50%

Did not pass.

95%

80%

70%

100%

120% = 54 Gy 110% = 49.5 Gy 105% = 47.25 Gy 100% = 45 Gy 95% = 42.75 Gy 90% = 40.5 Gy 80% = 36 Gy 70% = 31.5 Gy 50% = 22.5 Gy 25% = 11.25 Gy


Did not pass.

D2cm = Max Dose at 2cm from PTV > 90%



Did not pass.

50%



Did not pass.

50%



50% overlap

Did not pass.



Did not pass.



Passed on 2nd Try. Passed on 2nd Try.

2 Isocenter Plan passed on 2nd Try.


Passed on 2nd Try. 2 isocenters: passed on 2nd try.



2 isocenters: passed on 2nd try.













Passed on 1st try using VMAT.






Priority = PTV




Priority = PTV




Priority = Stomach




Priority = Stomach




90% connecting

Passed on 2nd try using VMAT.



100% connecting

Met DVA criteria but did not pass.



95% connecting

Met DVA criteria but did not pass.


NRG BR001: Benchmark Case 17 CyberKnife

95% of right PTV receives 48.6Gy Unacceptable

Deviation (< 42.5Gy or > 45.5Gy)




Did not pass.


D2cm = Max Dose at 2cm from PTV = 80%


Did not pass.


> 90%


Did not pass.


> 80%


Passed on 1st try.


D2cm = Max Dose at 2cm from PTV = 79%


Passed on 1st try.


> 95%

NRG BR001: Benchmark Statistics

• As of Jan 28, 2015:

– Benchmarks submitted = 22

– Benchmarks not passing but not yet re-submitted = 7

– Benchmarks passing = 15 • At 1st attempt = 8

• At 2nd attempt = 5

• At 3rd attempt = 2

• Sites completed all credentialing = 9!

• Satellites are required to submit benchmark.


• Treatment strategy:

– 1/15 treated with 2 separate plans to each lesion

– 1/15 delivered with CyberKnife

• Planning priorities:

– 4/15 spared stomach

– 11/15 treated PTV


• PTV volume (LT + RT) = 103 cc

• 95% dose volume = 128 cc (102-175)

• 80% dose volume = 211 cc (164-346)

• 70% dose volume = 279 cc (226-476)

• 50% dose volume = 519 cc (416-872)

• 105% dose volume = 39 cc (0-131)

• Max dose at 2cm = 71% (58-88%)

IGRT Credentialing Review




• Purpose: – To assess whether positioning with image-guidance will ensure

accurate PTV coverage

• How is this accomplished? – Assess description of IGRT workflow including threshold for correction

of translations & rotations

– Assess image quality (technique, FOV)

– Assess final treatment position relative to PTV margin required for protocol


• Potential issues encountered with 3D registration: – Table movement prior to acquiring CBCT

– Inter-observer variation


• Recommended data for 2D IGRT:

– 2D screenshots in addition to 2D DICOM images: • Reticule or scale

• PTV contours

• OAR contours (e.g., lung, spine)

– 2D OBI screenshots at final treatment position helpful

• Recommended data for 3D IGRT:

– Screenshots of in-house registration between CBCT & planning CT

• Reticule or scale

• 3D blending/subtraction

NRG BR001: 3D Spine IGRT Case 3 BrainLab ExacTrac

NRG BR001: 3D Spine IGRT Case 3

OBI kV


OBI kV





NRG BR001: 3D Spine IGRT Case 9 Axis X Y Z Institution Shifts -8.0 1.0 2.0 Reviewer Shifts -5.6 1.5 1.0 Difference -2.4 0.5 1.0


Axis X (mm) Y (mm) Z (mm)

Institution’s Shifts -8.0 1.0 2.0

Reviewer’s Shifts -5.6 1.5 1.0

Difference -2.4 0.5 1.0

Rotational Differences < 2 degrees


NRG BR001: 3D Lung IGRT Case 9





Axis X (mm) Y (mm) Z (mm)

Institution’s Shifts 2.3 -4.6 6.5

Reviewer’s Shifts 1.6 0.1 -5.2

Difference 0.7 -4.7 -1.3

Rotational Differences < 2 degrees


Available Resources & Guidelines

NRG BR001: Potential Issues

• Treatment of nearby metastases with same fractionation scheme should be considered

• Doses > 105% for parallel organs?

• Limiting doses > 105% for IMRT/VMAT limits conformality?

• Treatment of stationary (i.e., spinal) metastasis with gating to accommodate composite planning?

• Technical challenges at single institutions – Example: VMAT cannot be delivered with gating

NRG BR001: Resources

• IROC website with DVA & FAQ documents

• Email PIs or physics PIs

• Feedback is welcomed!

Physics Challenges for Patients on NRG BR001

Martha M. Matuszak, Ph.D.

Medical Physics Co-Chair

Challenges

• Single vs. Multiple Isocenters

• 3D vs. modulated techniques

• Plan Priorities with overlapping OARs/PTV

• Composite plan dose evaluation

• Previously Treated Patients

What you’ll see

• Patients with 2 GTVs that are within 5 cm of each other

• Patients with 3 or 4 GTVs that may or may not have lesions within 5 cm of each other

– Up to 2 could be surgically removed, but the others (or all) treated with SBRT

What you’ll see

• GTVs may be in the following classes:

– Lung (peripheral or central)

– Mediastinal/Cervical node

– Liver

– Spinal/Paraspinal

– Osseous

– Abdomen/Pelvis

Single or Multiple Plan/Iso?

• Multiple plans/IGRT are recommended for lesions more than 10 cm apart

– Due to variability in setup and IGRT, including uncorrected rotations

• Lesions that are within 5 cm are likely more easily planned and treated with 1 plan and 1 isocenter

– Requires separate phantom credentialing

Separate Plans (8 cm apart)

Benefit of Separate Plans (Especially w/o a 6D couch)

Benefit of Separate Plans (Especially w/o a 6D couch)

Single Plan, Multiple PTVs

• Treatment planning may be simplified when targets are ~ 5 cm or closer – Inverse planning may

be beneficial when close to OARs

• Must pay close attention to IGRT

• Gradient Index will likely be out of limits

Multiple Plans, Multiple PTVs

• Geometry may be favorable for 2 plans if there is less overlap in the SI direction

• Less challenging for IGRT

• Must may close attention to composite dose evaluation and dose in between targets

Separate 3D Plans

Multiple Plans, Multiple PTVs

• Geometry may be favorable for 2 plans if there is less overlap in the SI direction

• Less challenging for IGRT

• Must may close attention to composite dose evaluation and dose in between targets IGRT good for both PTVs – a single plan

may have been better able to spare dose between targets

PTV

Planning Priorities when OARs overlap PTVs

1. Meet critical serial OAR (cord, cauda, sacral/brachial plexus) objectives

– Avoid dose >105% Rx in any overlapping organs** and outside of the PTV

2. Meet target coverage & conformity objectives

– Allow target coverage to drop to variation acceptable in overlap regions with sensitive OARs (bowel, esophagus, stomach)

– 70% Rx min dose required in PTV

3. Meet remaining OAR objectives

Cord

Bowel

Violation

PTV

Cord

Bowel

Acceptable

Rx Dose Cord Max Limit

PTV

Cord

Bowel

Acceptable

Rx Dose 70% Rx Dose

Cord Max Limit

Composite Plan Evaluation

• All OAR objectives must be evaluated on the composite plan

• Target objectives are evaluated on individual plans unless the site plans to treat the plans on the same day with the same isocenter and setup

– We do not want to count on dose overlap between 2 plans due to differences in IGRT

Composite Dose Evaluation

Same # of fractions for all plans

Different # of fractions for some plans

Single CT Make a composite plan and evaluate all OAR doses using

the 3 Fx OR 5 Fx table

If a 5 Fx plan contributes > 1 Gy to an OAR, use the 3 Fx dose

limits. This is very conservative

Multiple CTs

1. Try to avoid multiple CTs if at all possible 2. If using multiple CTs and there is any overlap of an OAR, CTs

should be done with the same immobilization and breath hold technique

3. Try to obtain an overlapping portion of the CT for rigid registration so dose in the overlap region can be evaluated for those OARs on a composite plan

4. Follow above rules for variable fractionation

Composite Dose Evaluation

• Note that only rigid registration is approved for dose summation on multiple datasets

– Very important to minimize any changes in position or breath hold technique between multiple scans

• Deformable registration procedures and credentialing are currently being formulated within the Medical Physics Subcommittee

Rigid Registration Between 2 Datasets

• Spine + Lung dataset in same immobilization device rigidly registered

Rigid Dose Overlay

• Since 1 Gy line isn’t overlapping, the individual fractionation limits can be used for all OARs

• Use the smaller fractionation limit for judging lung dose – If there are any questions of

violations in these situations, feel free to contact the PIs

Handling Prior RT

• Overlap with previously treated OARS should be managed with care

• Only prior RT approaching OAR limits is excluded

• Highly recommend using biological dose summation to ensure safe doses to OARs – contact PIs with any concerns

Any Questions or Unusual Cases?

• Please feel free to call or email us!

NRG BR001: A Transition to NRG BR002

Steven Chmura, M.D., Ph.D.

Principal Investigator


NRG-BR002

A Phase II/III Trial of Stereotactic Body Radiotherapy (SBRT) and/or Surgical Ablation

for Newly Oligometastatic Breast Cancer

Clinical Questions

• Can ablation of Oligometastases change the natural history of metastatic cancer?

• Better characterize Oligometastatic patients • Clinically and Biologically

• Appropriate selection for therapy

• Quality of life

Completion of NRG001 is essential for accrual to NRG002

Hypothesis

Phase IIr: Hypothesis: ablative local therapy all VISIBLE lesions with

systemic therapy -> signal for meaningful improvement in the PFS to warrant continuation to Phase III trial

“Rolls over” into Phase III with a sufficient efficacy signal for PFS (i.e.. Go / no Go)

Phase III: Hypothesis: Multi-Modality treatment of Oligometastases ->

superior 5y OS

OLIGOMETASTATIC BREAST CANCER Controlled Locoregional Disease and ≤ 2 Metastases

≤ 6 months systemic therapy without progression

STRATIFICATION 1 v >1 metastasis

Hormone receptor status Her 2 neu status

Chemotherapy for MBC ( yes or no)

RANDOMIZATION

ARM 1 Standard systemic therapy

Symptom directed palliative

therapy as needed

ARM 2 Total ablation of all metastases

Standard systemic therapy

Phase IIr – Eligibility

• Pathologic confirmation of MBC

• < 2 metastasis (< 4 pending NRG BR001)

• Local regional disease controlled (No Overlap with E2108)

• All metastasis amenable to SBRT or Resection (<5cm), No brain metastasis

• Zubrod performance status ≤ 2

Statistics (Phase IIr)

Primary Endpoint:

Demonstrate improved PFS with the addition of Ablative Therapy to SOC v. SOC

130 evaluable patients will provide 95% power to detect improvement in PFS from

10.5 months to 19 months (HR=0.55)

One-sided type I error of 0.15.

• PFS will be measured from the date of randomization to the date of first PFS

failure or last follow-up.

• Imaging q3 months for 2 years or until progression.

• After 2 years, imaging will be lengthened to q6 months or progression.

• After 5 years without progression, imaging per best clinical practice is recommended.)

Statistics (Phase III)

Primary Endpoint:

Demonstrate improved OS with the addition of Ablative Therapy to SOC v. SOC 246 additional evaluable patients for will provide 85% power to detect improvement in OS from:

28% to 42.5% (HR=0.67) One-sided type I error of 0.025. Total Phase IIR/III accrual: 402 patients. Integrated phase II/III design: 81% power for OS analysis at p= 0.025 (1-sided)

Minimal disruption to systemic therapy

• All SOC HT, Her 2, and bone drugs continue

• Experimental Tx need 30 day wash out

• Chemo hold prior to ablation is very liberal – (ie: 14-21 days for 14-28 day cycles, 7 days for weekly

regimens)

– TDM-1 and everolimus follow chemo holds

• Can resume held drugs 28 day post ablation (to allow for CTC blood draw)

For metastatic breast cancer,

Secondary Endpoints • Integrated science to include

– Circulating Tumor Cells (-14, post-SBRT, Progression)

– Banking of blood for ctDNA correlates

– Banking of blood to validate microRNA

• Integrated Quality of Life/PRO

– Testing hypothesis ablative therapy of all metastatic sites will result in less frequent disease-related symptoms and better functional status

Anticipated Outcomes • If Ablative Therapy of all Metastases improves

OS when added to standard systemic therapy, then the paradigm shifts to multidisciplinary treatment

• If Ablative Therapy of all Metastases does not improve OS when added to standard systemic therapy, then off-protocol use of SBRT stops • Cost reduction and toxicity avoidance

NRG BR002: Credentialing

• Sites that have credentialed for and treated a patient on BR001

Grandfathered!

• Sites that have credentialed for BR001 but never enrolled a patient

Pre-treatment review

• Sites that have not credentialed for BR001

Pre-treatment review + IGRT + IROC phantom

Acknowledgements: Steven Chmura, PI Joseph Salama, Radiation Oncology PI Martha Matuszak, Physics co-PI Thomas Pisansky, NRG GU Committee, Rad Onc Co-Chair Clifford Robinson, NRG Lung Committee, Rad Onc Co-Chair Julia White, NRG Breast Committee David Followill, IROC-Houston James Galvin, NRG Physics Committee Jessica Leif, IROC-Houston Susan McNulty, IROC-Philadelphia Robert Timmerman, NRG SBRT Committee Ying Xiao, NRG Physics Committee

Thanks to all participating institutions!

Documents

A Trial Introduction to NRG-BR001: A Phase 1 Study of SBRT ... Credentialing Materials/NRG... · A Trial Introduction to NRG-BR001: A Phase 1 Study of SBRT for the Treatment of Multiple