The Radiological Physics Center Quality Assurance in Clinical Trials

The Radiological Physics Center Quality Assurance in Clinical Trials David Followill, Ph.D. Director Radiological Physics Center

Radiological Physics Center •

Formed in 1968 by agreement between AAPM and Committee for Radiotherapy Studies (CRTS) chaired by G. Fletcher to monitor institutions participation in clinical trials

•

Funded continuously by NCI for 43 years even as structure of cooperative group programs have changed

Mission •

Assure NCI and cooperative groups that institutions participating in clinical trials deliver prescribed doses that are comparable and consistent. (Minimize dose uncertainty)

•

Help institutions to make any corrections that might be needed.

•

Report findings to the community.

Ideal dose delivery per protocol

Mission of the RPC is to minimize the dose uncertainty

Add errorinina dose Results No we have a less than orflatter delivery dose desirable dose distribution response curve within the cohort and thus lower response than expected

Pettersen et al 2008

Clinical Trial Participants Number of Active Institutions – 1,842 ~3,400 megavoltage machines ~22,124 active megavoltage beams Active Machines

2000

# of M achines

1800 1600

4000 3000

1400

1000

Year

09 20

03

01 0

06 20

Year

20

2 19 007 94 20 19 08 97 20 20 09 00 2

19 1 709 9

19 2 0 85 04 19 2 0 0 88 5 2 19 0 0 91 6

19 2 7300 0 19 2 7600 1 19 2 0 79 02 19 2 0 82 03

0

98

1000

2000

9

1200

19

# of Institutions

Active Institutions

l a c i n i l C

Trials

1842 Participating Institutions

CALGB ECOG

NCI

NCCTG ACRIN

COG

GOG

ACOSOG

NSABP

RPC

SWOG

QARC

ATC

RTOG RTOG

ITC

Clinical

NCI

Trials

Components of a QA Program Remote audits of machine output 1,842 institutions, ~14,000 beams measured with TLD and OSLD in North America and Internationally Patient Treatment record reviews Review for GOG, NSABP, NCCTG, RTOG (brachy) On-site dosimetry reviews 30 institutions visited (~150 accelerators/450 beams measured) Credentialing - Phantoms > 500 Phantoms irradiations in 2010

RPC Verification of Institutions’ Delivery of Tumor Dose Reference calibration (NIST traceable)

Evaluated by RPC Dosimeters

Remote Audits • Verification of Reference Calibration for photon and electron beams • Units of special design (Gamma Knife, CyberKnife, Tomotherapy)

Remote Audits TLD: ThermoLuminescent Dosimetry OSLD: Optically Stimulated Luminescence Dosimetry

OSLDs TLD

TLD vs OSLD •

LiF:Mg,Ti (TLD-100)

•

(Al2O3:C)

•

Disposable

•

Reusable (dose limit ~ 10Gy)

• One reading

• Re-readable

•

Temperature and weight control • .

No temp/weight ctrl, light tightness

•

3 dosimeters per point

2 dosimeters per point,

• 6 min reading time

•

• ~ 2 min reading time

• Dosimeter cost per check $2.40 • Dosimeter cost per check $1.00

Remote Beam Output Audits (OSLD)

928 institutions monitored in 2010 (10,707 beams)

130 institutions (14%) had repeats

OSLD audit has been efficient and cost effective BEAM CHECKS 6/1/10-1/10/11

X-ray

OSLD

TLD

1200 Photon Electron 1000

0.995 (1.6%) 0.998 (1.7%)

Electron 0.996 (2%) 6 mths

0.998 (1.9%) 5 yr

800 BEAM COUNT

Modality

600

400

200

0 0.91 0.92 0.93 0.94 0.95 0.96 0.97 0.98 0.99

1

1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.1

OSLD/INST

Need for Dose Audits Are there errors in beam calibration? Figure 1

Visited Institutions contribute ~85% of clinical trial patients

35% Percent of Institutions with TLD Outside Criteria

30% 25% 20%

VISITED NON-VISITED

15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year

RPC Verification of Institutions’ Delivery of Tumor Dose Reference calibration (NIST traceable) Correction Factors: Field size & shape Depth of target Transmission factors Treatment time


Evaluated by RPC visits and chart review

On-Site Dosimetry Review Visit The only completely independent comprehensive radiotherapy quality audit in the USA and Canada •

Identify errors in dosimetry and QA and suggest improvements.

•

Collect and verify dosimetry data for chart review.

•

Improve quality of patient care. 15

15

Dosimetry Review Visit Study of 1474 institutions participating in clinical trials correlating RPC visit with patient accrual visited Institutions: 771 Prioritization

not visited yet

838 schema Patient accrual:focuses 20,878our visit 3,313 resources (85%)where the (15%) majority of the patients are treated!

On-Site Dosimetry Review Audit (overview)

Select an institution with a high prioritization score

Pre-travel preparation (NIST traceable)

RPC physicist travels to the institution:

Measurements, interviews, documentation review

Exit Interview with Radiation Oncologist and Medical Physicist

Recommendations for resolving dosimetry discrepancies and implementation of proper QA techniques given during visit and in a report before leaving the institution

On-Site Dosimetry Review Audit BEAM CALIBRATION RPC Onsite Visits

Percent within 3% Criterion

100%

95%

90%

Photon Electron

Reference Beam Calibration 85%

Percent of Inst. with ≥ 1TG-21 beam out of Criteria (since 2000) Implementation 80%

Photons

TLD (±5%) 7-11%

Electrons

TG-51 Implementation

6-12%

75% Visits1975 (±3%)1980 ~13% 1985 ~15% 1990

1995 YEAR

2000

2005

2010

On-Site Dosimetry Review Audit Discrepancies Discovered (Jan. ’05 – Mar. ’10) Number of Institutions Receiving rec. (n = 156) 115 (74%)

Discrepancies Regarding: Review QA Program Photon Field Size Dependence (FSD) Wedge Factor (WF) Off-axis Factors (OAF)/Beam symmetry Electron Calibration Photon Depth Dose Electron Depth Dose Photon Calibration Review Temp/Press Correction Change to TG-51 Electron Cone Ratios Using Multiple Sets of Data

Monitor Units =

62 (40%) 50 (32%) 46 (29%) 27 (17%) 25 (16%) 18 (12%) 13 (8%) 11 (7%) 9 (6%) 8 (5%) 8 (5%)

Prescription Dose

(calibration) • (FSD) • (WF) • (depth dose) • (OAF)

Purpose of Treatment Record Review Maintain a low uncertainty in doses delivered to protocol patients by discovering and correcting errors Provide study groups with accurate dose data

Improve Clinical Trials

RPC Treatment Record Review

Independent calculation of tumor dose Agree within 5% for external beam (15% for brachytherapy) Verify dose, time, fractionation per protocol Notify institution if major deviation seen during review to prevent further deviations

Treatment Record Review Process Review of treatment records & forms for accuracy

Independent dose recalculation

Resolve errors by contacting institution

Discuss results with Group and Study Chair

Facilitate clinical review at Group meetings, RPC, HQ

Errors > 5% (>15%) Found in Dose Review • 1% Systematic errors • 8% Individual errors • 27% Dose Reporting errors

Actual patient dose error Transcription error

Without RPC review 36% of the reported doses used by the study group would be incorrect

RPC Verification of Institutions’ Delivery of Tumor Dose Reference calibration (NIST traceable) Correction Factors: Field size & shape Depth of target Transmission factors Treatment time

Tumor Dose


Evaluated by RPC visits and chart review

Evaluated by RPC phantoms

Purpose of Credentialing • Educate • Improve understanding of protocol • Evaluate ability to deliver dose • Improve treatment delivery

• Reduce the deviation rate

Non-Credentialed Protocols (closed studies) Study

Disease Site

GOG 0122 Endometrial (1992) NSABP B14 Breast (1981) RTOG 9001 Cervical (1990) RTOG 9003 Head & (1991) Neck

Major Deviations

Minor Deviations

Number of Patients

29 (15%)

37 (19%)

197

135 (9%)

214 (15%)

1460

43 (14%)

76 (24%)

315

75 (7%)

188 (18%)

1073

Results of Credentialing Study

Disease Site

Major Deviations

Minor Deviations

Number of Patients

COMS

Eye

43 (5%)

47 (3.6%)

1166

GOG 165

Cervix

0

15 (21%)

70

RTOG 95-17 HDR & LDR

Breast

0

4 (4%)

100

RTOG 0019 LDR

Prostate

0

6 (5%)

117

3 (0.3%) 0 0

121 (10%) 42 (12%) 8 (9%)

1171 348 93

NSABP B39/RTOG 0413 3D MammoSite MultiCatheter

Breast

Use of Advanced Technologies in clinical trials? TRACKING

IMRT

MV R O KV

G N I GAT S

T R B

Re spi rat Co ory ntr ol

IGRT

TPS IMR T D O SE H ET PAI ER O NTI NG COR REC TIO N

Imaging, Planning and Delivery QA required at each step Positioning and Immobilization

Image Acquisition (CT, MR)

Structure Segmentation

treatment planning

Black Box File transfer and management

Plan validation

Position verification

treatment delivery

What You See Is NOT What You Always Get

RPC Phantom family 10 prostate phantoms (Photon IMRT/Protons)

8 Spine phantoms

31 H&N phantoms (IMRT)

14 thorax phantoms (Photon SBRT/IMRT) Proton head phantom and Protons

RPC Phantom Design • Anthropomorphic shape

Phantom

Patient

• Water filled • Plastic inserts containing targets and organs at risk (heterogeneity) • Point dose (TLD) and planar (radiochromic film) dosimeters • Purpose is to evaluate the complete treatment process from imaging to planning to setup to delivery

Patient

Phantom

Number of Phantom Mailings

400 Spine SRS Head

300

Liver Prostate Lung

200

H&N

100 0

2 0 0 1 2 0 0 2 2 0 0 3 2 0 04 2 0 05 2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 10

Phantoms Mailed

500

Year

Plan vs. Treatment

Good Agreement Primary PTV

Secondary PTV

OAR

Measurement

Plan

Examples of Failures

Measurement vs. Monte Carlo Criteria 3%/2 mm 0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2.0

L

700 680 660

Dose DoseValue Value

640 640 620 620 600 600

L

R

580 580

LATERAL

560 560 540 540 520 520 0 0

Calc Calc Meas Meas 10 10

20 20

30 30

40 50 60 40 50 60 Distance along line Distance along line

70 70

80 80

90 90

P Axial

Varian 6 MV IMRT H&N 36

Good Agreement PTV OAR Cord/bone

Measurement

Plan

Bad Agreement

PTV

OAR Cord/bone

RPC Lung phantom

Convolution R-L Profile Right Left Profile Axial plane Left

Righ 30

Average displacement Left side: on: 3 mm off: 1 mm Prescribed D

Average displacement Rigth side: on: 1 mm off: 5 mm

Dose (Gy)

20

D2cm 10

PTV 0 -7

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

6

Distance (cm)

RPC Film

ITC off

ITC on

RPC Regression

Institution Regression

7

Pencil-Beam Profile Right Left Profile Axial plane 30

Left Average displacement Left side: on: -2 mm off: -6 mm

Right Average displacement Right side: on: -5 mm off: -2 mm

Prescribed D

Dose (Gy)

20

D2cm 10

PTV

0 -7

-6

-5

-4

RPC Film

-3

-2

ITC off

-1

0

Distance (cm)

ITC on

1

2

RPC Regression

3

4

5

Institution Regression

6

7

CyberKnife ray-tracing Algorithm • Initial results were unsatisfactory • TLD measured doses in the center of the PTV to be ~13% low compared to calculated values. • Profiles were correct shape, but wrong absolute dose.

GTV PTV

Film 1 Film 2 Film 3 Film Avg TPS +5%/3mm -5%/3mm

11

Right-Left Profile Axial plane Left

CyberKnife Monte Carlo

Right

Average displacement Left side: Prescribed D 1 mm

Average displacement Right side: 2 mm

8

D o s e (G y )

6

D2cm

4

2

PTV

•

Average TLD RPC/Inst = 0.985

0 -7

-6

-5

-4

-3

-2

-1

0

Distance (cm)

1

2

3

4

5

6

7

Lung Phantom TLD results TLD results All algorithms 1.06

Average = 0.966 (sd 2.6%) 231 irradiations ( no outliers included)

1.04

RPC/Inst

1.02 1.00 0.98 0.96 0.94 0.92 0.90

0

50

100

Irradiation number

150

200

Lung Phantom TLD results TLD results (MC shown)

1.06

MC Average = 0.996 (sd 2.5%) 28 irradiations ( no outliers included)

1.04

RPC/Inst

1.02 1.00 0.98 0.96 0.94 0.92 0.90

0

50

100

150

Irradiation number

200

Phantom Results Comparison between institution’s plan and delivered dose. Phantom

H&N

Prostate

Spine

Lung

Irradiations

961

234

61

337

Pass Pass Fail Fail Criteria

686 (79%) 162 (82%) 22 (63%) 178 (75%) Static Motion 765 (80%) 187 196

196 (84%) 36 (59%) 268 (80%) 35 59 56 (84%) Pass 13221 (79%) 38 25 69 7%/4mm 7%/4mm Fail 5%/3mm 605%/5mm 13

Decrease RTOG Inst.the criteria to 5%/3mm for all phantoms and 440 (52%) 132 (15%) 36 (4%) 216 (25%) Acceptable Number of failures DOUBLES

>80% Pass Rate RPC H&N and Lung Phantoms

Percent of Passing Irradiations

100

80

H&N

60

lung 40

20 2003

2004

2005

2006

2007

Year

2008

2009

2010

Proton therapy facilities

Presently 9 clinically-active US proton therapy centers wanting to participating in clinical trials

new centers expected to open this coming year

Several trials in development to allow protons

NCI provided funds for a consultant to refine visit procedures and lead visits to 5 centers during 2010 and 4 more in 2011

Proton Facility Approval

Proposed RTOG/NCI Guidelines require: Questionnaire - Completed by 8 sites

TLD monitoring Mailed to 9 US centers + 1 Japanese center

On-site dosimetry review visits 3 visits (MDACC, UF and MGH) completed 2 visits (Penn, IN) completed, reports being generated

Anthropomorphic phantoms

Irradiated by 5 sites (3 passed, 1 failed, 1 under analysis)

Modifications to existing phantoms for other protocols

Proton Beam Monitoring Most measurements at mid-SOBP ± 2 cm

Phantoms HU RSP Calibration Curve

Pelvis phantom was modified2

1.8 Irradiated at 5 facilities 1.6

Lung phantom modified RSP

Irradiated at 2 facilities

head phantom developed

Tested at MDACC

1.4 1.2 1 0.8 0.6 0.4 0.2 0

-1500

-1000

-500

0

500

1000

1500

HU Eclipse PBT-poly B100 EBT2 Presage

Acrylic HI Poly C552 Solid Water

Polyethy/Wax PVC D400 Waxy*

Nylon Water Blue Water Balsa

Polyethylene A150 Epolene Cork

2000

Lung Phantom

Brain Phantom

Selected Phantom Lab “Alderson” phantom

Materials fall on CT#-RLSP curve

Contains realistic bony anatomy

Inserts with target and dosimetry will be constructed

•MR image to define CTV •MR image fused with CT for prescription and dose calc.

Phantom Accomplishments 1.

2.

3. 4.

Setting a standard for IMRT use in clinical trials Use of heterogeneity corrections for modern algorithms Test ability to hit a moving target(s) Testing proton therapy planning and dose calculations (in development)

The RPC, with its established infrastructure and experience, is a unique resource to the clinical trial setting as well as to the Radiotherapy community. We are confident that RPC QA audits through detection, education and correction have maintained if not reduced the uncertainty in the doses delivered to trial patients and improved the safe delivery of radiation doses to many other patients.

Systematic Errors >5%(>15%) Problem

Magnitude

TPS used wrong depth when head frame used

27%

Lung correction used, not allowed on protocol

9 – 13%

TPS wedge factor differs from clinical wedge factor

9%

TPS did heterogeneity corrections incorrectly

8.5%

Non-measured output with average TLD > 5%

7%

Point of calculation on edge of field

7%

Institution didn’t used effective field size when >50% of the field was blocked

5%

Individual Errors >5%(>15%) Problem Incorrect prescription points on brachytherapy Reported dose rates rather than dose for brachytherapy

Magnitude Up to 553% Up to 480%

Magnification error on brachytherapy Combined with incorrect prescription point

144% 208%

Hand written daily treatment record differed from Record and Verify for one field Brachytherapy shielding error Dose reported under block for parametrial boost

145%

Inhomogeneity corrections used (not allowed on protocol)

5 - 7%

23% 21%