Radiation oncology

Lecture 15-16

Early cures. In 1899, in Stockholm, Thor Stenbeck initiated the treatment of a 49-year-old woman's basal-cell carcinoma of the skin of the nose (above), delivering over 100 treatments in the course of 9 months. The patient was living and well 30 years later. Many patients marveled at the experience of receiving radiations.

Extraordinary follow-up. In November 1896, Leopold Freund in Vienna irradiated a four-year-old girl with an extensive dorsal hairy nevus. Although the immediate

result was a painful moist radioepidermatitis, permanent regression followed. The young woman led a normal life, bearing a healthy son. Photographs taken at 74 years

of age, however, reveal lumbar skin scarring, kyphoses, keratoses, and sequelar osteoporosis.

Early radium treatment. The painstaking process of extracting minute amounts of radium from tons of ore made the element extraordinarily rare and expensive in these earliest years. The Curies loaned small amounts to various Paris physicians, including Louis Wickham and Paul Desgrais who in 1907 treated this child's erectile angioma using a crossfire technique. Below, early applicators were devised in a number of shapes and

sizes-flat for surface work and cylindrical for intracavitary use.

1 MeV Metropolitan Vickers Unit, St. Bartholomew's, London, 1937. Dr. Ralph Phillips and physicist George Innes devised this 30' long X-ray tube and 600 kVp generator, with variable field sizes, moving couch, vacuum system, parallel plate monitoring, light field localization, and vertical/rotational capabilities. Others were soon in place in Seattle, New York, and

California.

First clinical van de Graaff generator, 1933-37. Robert van de Graaff devised a direct current electrostatic generator in 1929. A 2 MeV dedicated radiotherapy

unit installed at Huntington Memorial Hospital in Boston used the van de Graaff and boasted pre-treatment planning, wedge filters, and various orientations. The Royal Marsden unit shown had a turntable and set-up lines, but due to field size

and insufficient output was not clinically practical.

The physical goal of radiation therapy

From a physics perspective the goal of radiation therapy could be simply stated as

“Deliver a high dose to all parts of the tumor while minimizing the dose to surrounding normal tissue.”

100%

0%

As we will see, this ideal dose distribution is not physically achievable, but we attempt to satisfy it

through two general strategies: brachytherapy and teletherapy.

Brachytherapy The word is derived from the Greek word brachios meaning short and refers to the therapeutic

use of encapsulated radionuclides within or close to a tumor/target

In brachytherapy radiation sources are placed adjacent to orwithin the target volume. The sources may be implantedpermanently or temporarily. Temporary implants may be performed at high dose rate (HDR, treatment time of minutes) or low dose rate (LDR, treatment time of days). It involves use of nuclear radioactivity. We will not have time to discuss it later in the course. Just few illustrations.

Teletherapy uses the external sourses: photons, electrons, protons, ions.

The ultrasound guided probe, the needle, and the guide being applied in a treatment procedure for prostate cancer.

Develompent started right after discovery of radiactivity. Hiatus in the middle of the 20th Century due to high risk to practitioner and patient. New technology later in the century, brachytherapy has re-emerged as a leading treatment option in the past three decades

Below is a sample seed that would be used in a brachytherapy treatment procedure. Its relative size is indicated by the background finger that is holding it.

In teletherapy an external source at a distance of about one meter from the patient is used to irradiate the tumor. A series of daily fractions, each about 2 Gy, is used. It takes about one minute to deliver the actual treatment, but typically 15 minutes to position the patient

and deliver beams from different directions.

P1

P2

Source

r2 r1

d1

d2 For normal tissue closer to the source, both attenuation and the inverse-square law work against achieving an

acceptable dose distribution. However, the advantages of

using teletherapy are many...

Advantages of teletherapy

1. Any anatomical site can be treated.2. Large fields (even the whole body!) can be accomodated.

3. Treatment is quick and convenient.4. Usually done as an outpatient procedure.

5. Noninvasive.6. Can be performed on patients who are not well.

7. No significant radiation dose to staff, family members, etc.8. The physical disadvantages can be largely overcome.

Dose distribution from a photon beam

To understand #8 above, we need to understand the dose distribution from an external photon beam. We need to consider:

1. Dose is due mainly to electrons.2. Electrons have finite range.

3. Attenuation of primary photons.4. Inverse square law.

5. Compton scattered photons.

Simple model for dose near the surface...

Assume each high energy electron is launched in the forward direction and that each has the range shown. The dose in each layer of tissue will be proportional to the number of

electron tracks per unit volume. If there is no substantial attenuation of the photon fluence over this distance we would expect:

D2 = 2D

1, D

3 = 3D

1, D

4 = 4D

1, D

5 = 5D

1, D

6 = 6D

1,

but after this layer (in which we reach an equilibrium in electron fluence), the dose would be approximately constant. But as depth continues to increase the photon fluence will

decrease due to attenuation.

Build-up region

Approx. exponential attenuation

Depth

Expectations of a naive

model:

Energy deposition for different photon energies

Skin effect increases with increase of the photon energy

Depth in mm

Here are some example of real depth-dose curves. Our simple model does predict the general nature of these curves, but not the quantitative details.

Depth in cm

Skin effect - difference between kerma = kinetic energy release in the media, and

absorbed dose.

Very important conclusion: smaller absorption (smaller μ )

- better the ratio between the dose in the tumor and in the healthy tissue. μ drops with increase of

the photon energy.

Use of high-energy electrons to generate photons - main mechanism is

bremsstrahlung. Electrons stop in a metal target and photons with continuum

distribution over the energies are produced. Average photon energy is about 1/3 of the

electron energy. Need electron beams of the energies up to 25 MeV.

In the case of a tumor deep inside the minimal amount of radiation obtained by the healthy tissue is in the ratio of

the volumes of the body and the tumor, that is >> 1.

An electron linear accelerator uses microwaves propagating in

a special waveguide to accelerate the electrons. The largest linac

accelerates electrons to 50 GeV, but medical accelerators operate in the 4

- 25 MeV range. As shown in the figure, the electron beam is focused

onto a metal target (usually tungsten). At high energies the

bremsstrahlung beam is forward peaked, so a metal “flattening filter” is

used to produce a more uniform beam. A set of moveable collimators allow the user to define rectangular beams of dimensions from 4 to 40

cm. An ionization chamber measures the radiation output in real time and

is one of the means by which the dose to the patient is controlled

The Varian Medical Linear Accelerator

Generates high energy X-rays for therapy

Rotates around the patient to deliver radiation from multiple beam angles

Works in special treatment room with 7-ft thick walls

Weighs ~ 18,000 lbs Measures 9 X 15 feet

Klystron

Axis of rotation

Axis of rotation

When the beam is not on, a light field is projected onto the patient which is coincident

with the radiation field. This aids in patient setup. Other devices, such as wall-mounted lasers are used in conjunction with marks on

the patient. Note that rotation of the entire accelerator assembly allows a photon

beam to be directed at the patient at any angle without moving the patient. This is

called an isocentric setup.

Typical teletherapy installation.

Because even the scattered and leakage radiation dose ratesare quite high in the room, only the patient can be present during

the actual irradiation. A specially designed shielded room (orbunker) is needed to protect staff and often the general public.

In a typical bunker for a high energy accelerator the primaryradiation barriers (see above) are about 2 m thick! These roomsare fairly expensive to build. Total cost of room and accelerator

is in the 2 - 4 million dollar range.

Primary barrier

Fundamental problem: task is to kill most of the tumor cells. However , if it is not close to the

surface to do this by shooting the beam from one direction would require a sure kill of all cells along

the beam path.

With increase of the photon energy the problem becomes

less severe

Consider what happens if you use two beams entering the patient from opposite directions. The resulting dose distribution will be the sum of the contributions from the two fields. Plotting the dose along the central axis of this opposing pair of fields

we get something that looks like

Even with this simple arrangement we can get more dose in a deep-seated tumor than in the over-lying normal tissue. This idea can be extended to more complex arrangements

ranging from standard 3, 4 or more field geometries to quite complex individualized plans that incorporate beam modifiers. However the total dose to healthy tissue is not

reduced it is merely spread!!!

We will discuss actual modern procedures later.

With a linear accelerator it may also be possible to extract the electron beam before it hits the thick target. This beam is usually scattered by a thin metal foil to produce a large, reasonably flat field. Recall that electrons have a finite range in tissue and thatdose is deposited in roughly equal amounts per unit pathlength. Therefore we might expect a broad electron beam to produce a depth-dose curve that is constant up to the range of the electron and then falls off rapidly. Real depth-dose curves show roughly these features:

Electron scattering is responsible for “blurring” of the sharp fall-off and also results in a relatively fuzzy edge to the beam.

These isodose plots show that the distribution tends to deterioratewith depth. Nonetheless, electron beams are very useful in

treating targets relatively close to the surface, especially whensensitive normal tissues (such as the spinal cord) lie directly

beneath the target volume.

This graph shows typical survival curves for mammalian cells. For x-rays, note the “shoulder” on the survival curve in the low dose region. Radiation is less effective in killing cells at low dose because the cell is capable of repairing some radiation damage. At higher doses the survival is approximately exponential as the survival decreases by a factor of 1/e for

each dose increment D0. For mammalian cells D0 is about 1 - 2 Gy.

Before discussing modern procedures of radiotherapy with photons we look again briefly at the biological effects relevant for oncological treatments.

Effect of oxygen on survival curves. Very important for treating large tumors in which many cells are hypoxic. One of the key reasons for using fractions.

Dividing the total dose to the fractions given for several days/ weeks. Between the fractions the

cancer cells which did not have oxygen and which survived the first fraction start to receive

oxygen since oxygen rich cancer cells were killed. Also repair does not work as well in many

cancer cells and they divide more frequently.

At a high enough dose we would have a high probability of curing every tumor. Unfortunately, this may also kill most of the normal tissue.

Progress in the tools of radiotherapy is closely correlated with the progress in diagnostic tools - without a good

knowledge of the position of the tumor precise delivery would be meaningless.

Simple treatment delivers uniform dose from 2-4 beam angles Beam shape is rectangular or squareBeam hits healthy tissue as well as tumorDoses have to be kept low to minimize harm to normal tissue

Pink = treatment field or area hit by beam

Primary collimator shapes beam

Conventional Radiotherapy - 1960s

Early Beam Shaping - 1970s

Blocks and wedges used to shape beams and begin sparing healthy tissue Blocks are changed by hand for each beam angleLabor intensive process requires therapist to visit treatment room repeatedlyTypical treatments use 4 beam angles Dose still relatively low

Roughly shaped treatment field

Wedge helps shape beam

3-D Conformal Radiation Therapy - late 1980s

Custom-molded block(s) match beam shape to tumor profile Beam shaping from multiple angles conforms radiation dose to tumor volumeTypical treatments use 4-6 beam anglesDose still relatively low Blocks still changed by handStill slow and labor intensive

Beam shaping automated with first multileaf collimators (MLC)Less labor intensive--no entering and exiting treatment room to change blocks Doctors use CT scans to see tumors in 3-D for more precise treatment planningTreatment uses 4-6 beam angles

Introduction of themultileaf collimator

Automated 3-D Conformal Radiation Therapy (CRT)

Divides each treatment field into multiple segments (up to 500/angle)

Intensity Modulated Radiation Therapy (IMRT) - mid 1990s

A Revolution inRadiotherapy

Allows dose escalation to most aggressive tumor cells; best protection of healthy tissue Modulates radiation intensity; gives distinct dose to each segment

Uses 9+ beam angles, thousands of segments

Improves precision/accuracy

Requires inverse treatment planning software to calculate dose distribution

Intensity Modulated Radiation

Therapy (IMRT)

with nine x-ray

beams

© Tony Lomax (PSI)

Early IMRT--Nomos

Patients must be moved to treat larger tumors.

Collimator is only 4 cm high

Beam shaping by a “MIMiC™” MLC device with 40 leaves Maximum field size 4 cm X 20 cm Minimum segments size is 1 cm X 1 cm Patient must be moved during treatment of larger areas

Problems: Low resolution Slow, uncomfortable (patient can be on couch 45-60 minutes per treatment) Noisy, nerve wracking

Today: SmartBeam IMRT

MLC becomes dynamic

MLC now covers 40 X 40 cm Up to 120 leaves Segments shrink to 2.5 X 5 mm No patient movement required

Uses “sliding windows” to speed treatment (10-15 min) and improve patient comfort

Makes IMRT efficient, cost effective, quiet

Treating Head & Neck with Sliding Windows

Images from theUniversity of Chicago Medical Center, Department of Radiation and Cellular Oncology

Prostate Cancer: Improved Outcomes

Dose Level Advanced Stage Complication Rate 2.5-Year Local (Grade 2 Bleeding) Control (Biopsy)

68 Gy 43% >6%

70 Gy 64% 6%

76 Gy 73% 17%

81 Gy – 3D CRT 96% 10%

81 Gy - inverse planned (IMRT) 2%

IMRT Plan for Vertebral Body Tumor

IMRT - A Complex Process involving a team of physicians, physicists and radiation

therapists (big shortage of physicists!!!) (see table next slide)

Planning

Plan Verification

Position Verification

target localization

Treatment Delivery

and Verification

Delivery

Structure Segmentation

Treatment Optimization

Patient Immobilization

CT/MRI/PET Image Acquisition allows to fix position of tumor with with precision

Tumor

Node #1

Tumor

Node #2

Tumor

Image Guidance (PET/CT) allows to determine accurately position of the tumor

Bite-block Head Holder

Immobilization

Aquaplast

Vacuum frame

Newest development : systems which adjust for breathings while delivering beams. Use of lasers, ....

Breath Control Spirometer

Treatment Delivery: Multileaf Collimator insures high transverse resolution

Beam Delivery with a MultiLeaf Collimator: resolution 2.5 x 5.0 mm

0.03 MU Dose Delivery

2.5 mm spatial longitudinal

5.0mm spatial lateral

Beam Delivery with a MLC

Intensity Modulation

No Intensity Modulation Intensity Modulation

Same Shape

Modulation of intensity allows to deliver equal doses to the parts of tumor which have different distance from the surface

Conventional Treatment Planning

Postulating a number of candidate radiation fields based on the planner’s experience; adjusting beam parameters manually to create a better dose distribution.

Inverse Treatment Planning

Dose prescription is given firstA set of intensity-modulated external

fields is generated through an optimization process

Principal difference of IMRT from conventional treatment (still used in 60-

70% of cases) is that Conventional treatment planning starts with a

set of beam weights and obtains aplan by a trial-and-error process.

This procedure won’t work for IMRT since there are too many unknowns (>2000 beamlet weights).

70%

80%

90%

!!

!

40%

Conventional Treatment PlanningForward Planning

70%

80%

90%

??

?

40%

!

IMRT Treatment PlanningInverse Planning

One solves a problem of minimizing a a certain function (functional) based on the desired dose to the tumor and

minimizing dose to surrounding area with different weights for sensitive organs. Many algorithms, many ways to choose the

functional form.

Example: Objective function

5.021 })]()()[({ rDrDrIC nr

pMn −= ∑

Dp

(r) is the prescribed dose

Dn

(r) is the computed dose at nth iteration

I(r) is the weight (importance) for each organ

r denotes 3D elements of the body

I(r)Assigning particular values of is

obviously the job of radiologist.

Di= Cij Wj

-- Weight for beamlet jwjCij

-- dose contribution in voxel i from beamlet j in an open beam

i

j

Dose Calculation for IMRT

•Total dose in voxel i

•Or dose in any voxel in a more generic form

jijnj

i WCD ∑−=

=1

i

j

CWD=

jijnj

i WCD ∑−=

=1

CWD =

Objective Function

Many techniques for calculation of the minimum - all techniques obviously

approximate - number of variables is huge. In any case input parameters have intrinsic errors.

One Monte Carlo algorithm which allows to include such features as dispersion over the

energy of the photons ANCOD extends GEANT3 event generator developed at CERN

for modeling detectors

Optimisation: Field Direction.

Beams directions. Beams intersections with voxels.

Lwe calculation. Voxels ordering: (i,j,k) n .

Volume total

Source

Field

Optimize

Iterative method used in ANCOD:

Dose required, in a specific voxel, is modified in each iteration.

We start our calculation of weight of a given beam without considering any correlation with the other beams, then the weight of the following beam is calculated taking into account the precedent one.

Once we have the first set of the fluence (flux integrated over the time) values, it is necessary to iterate many times to find the fluence values satisfying the best to requirements and prescriptions.

) voxel , beam ( dw) voxel(Dbeam

beamrequired ∑= ) voxel , beam ( dw) voxel(Dbeam

beamrequired ∑=

Dose

X

Y

Example of a treatment plan optimized with ANCOD++

Pixels along X

X

Pix

el le

long

de

YPix

els

alo

ng

Y

Dose u.a

X

DVH inside target

DVH outside target

∑ ∑ ⎟⎠

⎞⎜⎝

⎛−=

voxels

2

faisceauxfaisceau

voxelprescrite ) voxel , beam ( dwD) W(F ∑ ∑ ⎟

⎠

⎞⎜⎝

⎛−=

voxels

2

faisceauxfaisceau

voxelprescrite ) voxel , beam ( dwD) W(F

Tomotherapy: A “revolution” in radiation therapy

Tomotherapy - slice therapy.Two approaches currently developed: serial

tomotherapyby NOMOS corporation and helical tomotherapy by

University of Wisconsin based group.Serial tomotherapy: fan beam of maximal width of 20 cm.

Multileaf collimator produces pencil beams of two shapes 0.8 x 1 cm and 1.6x 1 cm.

Helical tomotherapy Geometry of 4th generation CT

scanner.Combination of a helical CT scanner and a linear

acceleratorBeam from accelerator is collimated by

Multileaf collimator generating pencil beams of 6.25 mm x 6.25 mm

and width of 20 cm.

Imaging uses at least for now high energy photons. Continuos imaging allows to adjust for changes in the position of the tumor from one exposure to another.

http://www.tomotherapy.com/video/entry/tomotherapy_animation

Axial, Coronal, Saggital views of IMC/Breast delivery. Top row: Tomo Delivery,

Bottom row: Tangents, plus IMC photons and electrons (5 -field).

Example: Conformal dose to breast & Internal Mammary Chain (IMC)

QuickTime™ and aCinepak decompressor

are needed to see this picture.

Cyberknife, Stanford

Right anterior oblique 3D image showing 90 CyberKnife isocentric treatment positions and their relative intensities. The single fraction isocentric treatment in this case took 35 minutes.

208 beam positions for the treatment of this optic apparatus meningioma

demonstrates both the non-isocentric flexibility of the CyberKnife System for treatment of the tumor. In this case the

patient was treated with 5 fractions over 5 days at 40 minutes per fraction.