Future Developments In Radiation Therapy For Prostate Cancer

Future Developments in

Radiation Therapy for Prostate

Cancer

Steven J. Frank, MD

Assistant Professor

Genitourinary and Head/Neck Sections

Division of Radiation Oncology

Rectal Fistula

Sinus tract vs fistula

Rectal Necrotic Tissue

Biopsies showed

necrotic tissue

Dose-escalation is not free

• Rectal toxicity

• Urinary

• Erectile

Therapeutic ratio

Tumor control

Normal tissue complication

Total Radiation DOSE

Probability

of

EFFECT

Where are we going in

Prostate Radiation Therapy?

EBRT

• 2D

• 3D

• IMRT

• Hypofractionation

• SBRT

• Protons

• IMPT

Brachytherapy

• 1st Generation Implants

• 2nd Generation Implants

• 3rd Generation Implants

• 4th Generation Implants

• 5th Generation Implants

Where have we come from?

PSA control after conventional

dose RT (~70Gy)

IJROBP 2001;49

Higher RT doses improve

disease control

• Multiple retrospective studies show benefit to

higher doses of RT.

– MDACC (Pollack & Zagars. IJROBP 39, 1997)

– Fox Chase (Hanks et al. IJROBP 41, 1998)

– MSKCC (Zelefsky et al. IJROBP 41, 1998)

– MSKCC (Zelefsky et al. J Urol 166, 2001)

– Cleveland Clinic (Lyons et al. Urol 55, 2000)

More Grade 2 rectal complications in 78 Gy arm

[IJROBP 53, 2002]

More Grade 2+ rectal toxicity

if >25% of rectum received 70Gy

Dose-escalation w/ less

toxicity• Delivery techniques

– IMRT

– Protons

• Reduce PTV– Target localization (e.g. BAT, fiducial markers)

– Target immobilization (e.g. rectal balloon)

– Reduce CTV

• Selective dose-escalation– Intra-prostatic targets and avoidance structures

Axial Dose Distribution

75.6 Gy

60 Gy79 Gy

Sagittal Dose Distribution

Prostate:

>100%V@75.6Gy

SV:

>95%V@75.6Gy

Rectum:

<20%V@70Gy

<35%V@60Gy

Bladder:

<25%V@70Gy

<35%V@60Gy

Femoral Heads:

<5%V@50Gy

DVH

MSKCC

Rectal toxicity (3D CRT vs. IMRT)

3DCRT

IMRT

MSKCCGU toxicity based on dose 81 vs. 86 Gy

“Among patients who received doses 75.6 Gy, the incidence

of Grade 2 urinary symptoms at 5 years was 13% compared 8%

at lower doses.” [IJROBP 53, 2002]

Dose-escalation w/ less

toxicity• Delivery techniques

– IMRT

– Protons

• Reduce PTV

– Target localization (e.g. BAT, fiducials)

– Target immobilization (e.g. rectal balloon, tracking)

– Reduce CTV

• Selective dose-escalation

21

Accelerator Systems

Linac Injector

Synchrotron

13 m diameter190 tons SAD 2.7 m

Nozzle

Snout

Couch

Image

Receptors

X-ray

tube

Articulating Floor

A Single Bragg Peak

Modulation of the Bragg Peak

The Bragg peak is spread out by introducing extra absorbing material before the beam enters the patient. If different thickness of such absorber are present for different fractions of the irradiation time, the narrow monoenergetic peak can be spread into a useful plateau

The Bragg peak can be spread out

to a useful plateau by the use of a

rotating stepped absorber.

Range

Modulator

Wheel

SOBP, Photons, & Bragg Peak

PSI

Aperture 2D Shaping

Lateral aspect of aperture used

to spare critical structures

Compensator 3D Distal

Shaping

As well as spreading out

the Bragg peak, the final

range itself must be

shaped to the distal

surface of the target

volume taking into account

heterogeneities

Two lateral beams.

Further improvements w/ IMPT?

Decreased integral dose.

Better dose homogeneity.

Quicker planning time.

Dose-escalation w/ less toxicity

• Delivery techniques

– IMRT

– Protons

• Reduce PTV

– Target localization (e.g. BAT, fiducials)

– Target immobilzation (e.g. rectal balloon)

• Selective dose-escalation

Sharp dose-fall off with IMRT requires

accurate DAILY target localization

25 treatment CTs

Acquired during a course

of 42 fxs treatment

Dancing Prostate

Dong (MDA), 2002

IGRT is a Process

VARIAN

Reducing PTV a.k.a.

IGRT (Image Guided Radation Therapy)

• Improve accuracy and decrease normal

tissue irradiated

• Requires daily imaging of the target

• INTER-fractional movement

• INTRA-fractional movement

IGRT

• Portal imaging

• Ultrasound (e.g. B.A.T.)

• Fiducial markers (intraprostatic)

• Volumetric on-board imaging

– In-room CT

– Cone-beam CT

BAT alignment (axial)

Bladder

Prostate

Rectum

BAT Alignment (sagittal)

Bladder

Prostate

Rectum

Ultrasound-based alignment

• Pros– Non-invasive

– Reasonably good alignment

– Visualize SV/ bladder/rectum

– Visualize prostate surface contour

– Follow-up

– New volumetric systems

• Cons

– User-subjectivity

– Patient anatomy may

affect image quality

– Impact of probe

pressure on prostate

position

– Different imaging

modality

On-Board Imager (OBI) - Varian

kV X-ray Source

aSi Imaging Panel

(2048 x 1536 pixel resol.)

Robotic Arms

- 3 pivot points

- Completely retractable

- Position feedback control

Software

- Image acquisition and registration

OBI 2D-2D manual match: pre-shift

OBI 2D-2D manual match: postshift

Fiducial-based alignment

• Pros– Less subjectivity

– Good alignment

– Allows target tracking

• Kitamura and Shirato et al.

– Better for large patients

– Basis for improved multimodality image fusion (e.g. MRI-CT)

– Ongoing MDACC study comparing fiducials vs. CT-on-rails

• Cons– Invasive

– Requires daily ports

• (unless KV imaging onboard)

– No image of SV, rectum/bladder

– No image of prostate surface contour

– Shifts may not be representative of volume

• Jaffray et al. ASTRO 2004

• Fiducials and MRI

• 47% had 3mm deformation over 90% of surface

• On average, 14% of surface deformed by >3mm (up to 9mm)

Varian ExaCT™ at MDACC

In-room CT Linac

CAT Software (3D-3D matching)

Compares Pinnacle planed patients

to volumetric images

Lei Dong, Lifei (Joy) Zhang

A closer look at contour overlay

Courtesy of Lei Dong

Step 4. Automatic Image Registration

Courtesy of Lei Dong

Step 5. Review Image Registration

(prostate is the target of alignment)

Courtesy of Lei Dong

• CT-based alignment could yield

accuracy of <3mm

– Smaller treatment margins

– Less dose to rectum, bladder

– Avoid high-dose to intra-prostatic

structures (e.g. urethra)

Robotic arm motion

Robotic arm motion

Robotic arm motion

Cone-beam CT

• Uses on board kV X-ray source and

amorphous silicon flat panel imager

• Large field of view (25 x 25 x 10 cm) and

single revolution captures images

– Unlike standard CT that uses small field of view

and many revolutions

• Inferior image quality compared to

conventional CT but may be adequate for RT

targeting

Cone Beam CT – Large GU patient

(330 lbs)

CBCT Planning CT

Post shift CBCT verification

using in-house CAT software

Cone Beam CT vs. CT on Rails

< 5 min acquisition and

reconstruction time

Patient is rotated into scanning

position on treatment couch (lateral

and vertical shifts required)

Isocenter not linked to images

Each slice is a 1 sec time average

50 cm FOV (full scan)

< 5 min acquisition and

reconstruction time

Patient is imaged in treatment

position (except for lateral shifts)

Isocenter defined in CT space

Each slice is a 60 sec time average

45 cm FOV half-scan

Dose-escalation w/ less toxicity

• Delivery techniques

– IMRT

– Protons

• Reduce PTV

– Target localization (e.g. BAT, fiducials)

– Target immobilzation (e.g. rectal balloon)

• Selective dose-escalation

– Intraprostatic GTV/OAR

Endo-rectal balloon

1. Immobilize prostate (accounts for inter-

and intrafractional motion)

2. Displaces rectum away from high dose

Shifts Detected By CT and BAT

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

CT Shift (cm)

BA

T S

hif

t (c

m)

RL

AP

SI No call

by BAT

Planning CT Sagittal

Same Day Sagittal CT

Same Day Axial CT

BAT Oblique Axial Sagittal

One Patient

Example

Sup.

Sup.

Is intra-fractional prostate motion a

concern?

• Daily IMRT treatment 15 minutes to setup and deliver

• Possible prostate positional change during this interval largely due to transient rectal gas

• Positional change can be large (>5 mm), but usually transient

• Clinical impact over 7-8 week treatment course is unknown

Dose-escalation w/ less toxicity

• Delivery techniques

– IMRT

– Protons

• Reduce PTV

– Target localization (e.g. BAT, fiducials)

– Target immobilzation (e.g. rectal balloon)

• Selective dose-escalation

– Intraprostatic GTV/OAR

What is needed to treat intra-

prostatic targets?

• Imaging modality beyond CT that can delineate intra-prostatic tumor– Endorectal MRI/MRS

– Dynamic contrast MRI

• Conformal delivery method– IMRT, protons, brachytherapy

• Accurate delivery– Daily imaging w/ online correction

– Target immobilization?

– Transrectal U/S guidance

Endorectal MRI

• Endorectal MRI uses a coil inside an inflatable latex balloon (50-70cc).– Coil just posterior to

prostate

• Resolution is 0.4mm per pixel pair– Body coil MRI has

resolution of 3 mm

• Accuracy is technique and reader dependent as per RDOG studies

– [Radiology 1994;192:47-54]

[Roach et al. Oncology 15:1399-1410]

Special thanks to Danny Tran & Lei Dong

75.6Gy

87.2Gy

Concomitant

boost

CT/ MRI/MRS fusion

• Define CTV more clearly

– Prostate anatomy

– Reduced side effects

• Define other CTV’s (e.g. peripheral zone, urethra)

– Selective dose-escalation (“Dose painting”)

– Reduce toxicity w/ in the prostate

• Define GTV

– Selective dose-escalation (Focal boost)

Hypofractionation

• Provide basis for larger fractional dose w/

equal or less toxicity

– / for prostate ca may be < 4 Gy» [Brenner et al. IJROBP 52:6-13]

• Hypofractionation studies:

– Kupelian et al 70 Gy (2.5Gy/Fxn) [IJROBP 53, 2002]

– MDACC ongoing randomized study

• 75.6/1.8 Gy vs. 72/2.4 Gy (BED = 78-82 Gy)

72 Gy (2.4Gy)

Cleveland Clinic-retrospective70Gy/2.5Gy vs. 78Gy/2Gy

Grade 2-3 rectal toxicity

Kupelian et al. IJROPB 53, 2002

166 (SCIMRT)

116 (3DCRT)

Median FU 21 vs. 32 mo

Only 2 pts in each group

had Gr 2+ GU toxicity.

Highest Degree of Conformal

Therapy?

Brachytherapy

1st Generation Implants:

Open Placement

Transperineal Interstitial Permanent

Prostate Brachytherapy

Ultrasound probe in

rectum for needle guidance

Perineal template to

localize needles as planned

18 gauge needle

(1.3 mm diam) for

seed placement

2nd Generation Implants:

Uniform Loading

Source Migration

Davis BJ et al., J Urol 2002; 168:1103.

*

*Coronary

artery

3rd Generation Implants

• Modified peripheral loading

– Reduced urethral dose (not urethral sparing)

– All seeds implanted in the prostate

(which means little treatment outside capsule

or high urethral dose with margin)

– CT-based dosimetry evaluation

Modified Peripheral Loading

4th Generation Implants

• Stranded seeds (Varistrand )

– Less seed migration

– Permits periprostatic seed placement

• Improved dosimetry

– Wider therapeutic margin on prostate (3 - 5

mm)

– MRI / CT fusion (better QA better implants)

– Improved Homogeneity

Intraoperative Comparison of Actual Seed Location to Preplan

PTV DVH Parameters

V100>95%

V150<60%

V200<20%D90<120%

R100<1cc

5 yr BRFS Monotherapy

• Seed monotherapy 5 yr BRFS if implant

quality questionable or poor = 34-63%

• Seed monotherapy 5 yr BRFS if implant

quality is good = 82-98%

• % positive Bx cores predicts RP BRFS

• RTOG-0232 randomized study I125/Pd103 +/-

EBRT intermediate risk patients

Transperineal Interstitial

Permanent Brachytherapy

Alone for Selected Patients

with Intermediate Risk

Prostate Cancer

Phase II Prospective Single Arm Study

David Swanson and Steven J. Frank

Stratification

• < 35% core biopsy and Gleason 7 disease

with a PSA under 10

• < 35% core biopsy and combined Gleason

scores less than 7 with a PSA 10-15

• >/= 35% core biopsy and Gleason 7 disease

with a PSA under 10

• >/= 35% core biopsy and combined Gleason

scores less than 7 with a PSA 10-15

MRI vs. CT

July 2008

Front view Front view

Notice the artifacts on CT imaging

Prostate Phantom Prostate Phantom

1.5T MRI Strand

Prostate Phantom

C4

Seed

Prostate Phantom

Oblique view Saggittal view

GU Team

• Physicians

– Seungtaek Choi

– Min Rex Cheung

– Deborah A. Kuban

– Andrew K. Lee

– Jim D. Cox

– Tom A. Buchholz

• Physicists

– Lei Dong

– Rajat Kudchadker

– Jennifer Johnson

• Dosimetrists

– Paula Berner

– Teresa Bruno

– Mandy Cunningham

• Therapists

• Nurses