Early cures. In 1899, in
Stockholm, Thor Stenbeck initiated the treatment of a 49year-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 sizesflat 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.”
0%
100%
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.

Teletherapy uses the external sourses: photons, electrons, protons, ions.
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 or within the target volume. The sources may be implanted permanently 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.

Develompent started right after discovery of radiactivity. Hiatus in the middle of the 20 th 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
The ultrasound guided probe, the needle, and the guide being applied in a treatment procedure for prostate cancer.

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.
Source r
2 r
1
P
2 d
2 d
1
P
1
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.

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:
D = 2D
1
, D = 3D
1
, D
4
= 4D
1
, D
5
= 5D
1
, D
6
= 6D
1
, be approximately constant. But as depth continues to increase the photon fluence will decrease due to attenuation.

Expectations of a naive model:
Build-up region
Depth
Approx. exponential attenuation

Energy deposition for different photon energies
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
Depth in mm
Skin effect increases with increase of the photon energy

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.
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.
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.

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

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.
Primary barrier
Because even the scattered and leakage radiation dose rates are quite high in the room, only the patient can be present during the actual irradiation. A specially designed shielded room (or bunker) is needed to protect staff and often the general public.
In a typical bunker for a high energy accelerator the primary radiation barriers (see above) are about 2 m thick! These rooms are fairly expensive to build. Total cost of room and accelerator is in the 2 - 4 million dollar range.

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 that dose 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 falloff and also results in a relatively fuzzy edge to the beam
.
These isodose plots show that the distribution tends to deteriorate with depth. Nonetheless, electron beams are very useful in treating targets relatively close to the surface, especially when sensitive normal tissues (such as the spinal cord) lie directly beneath the target volume.

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

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 .
Conventional Radiotherapy - 1960s
Pink = treatment field or area hit by beam
Simple treatment delivers uniform dose from 2-4 beam angles
Beam shape is rectangular or square
Beam hits healthy tissue as well as tumor
Doses have to be kept low to minimize harm to normal tissue
Primary collimator shapes beam

Early Beam Shaping - 1970s
Roughly shaped treatment field
Wedge helps shape beam
Blocks and wedges used to shape beams and begin sparing healthy tissue
Blocks are changed by hand for each beam angle
Labor intensive process requires therapist to visit treatment room repeatedly
Typical treatments use 4 beam angles
Dose still relatively low

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 volume
Typical treatments use 4-6 beam angles
Dose still relatively low
Blocks still changed by hand
Still slow and labor intensive

Automated 3-D Conformal Radiation Therapy (CRT)
Introduction of the multileaf collimator
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 planning
Treatment uses 4-6 beam angles

Intensity Modulated Radiation Therapy
(IMRT) - mid 1990s
Divides each treatment field into multiple segments (up to 500/angle)
A Revolution in
Radiotherapy
 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 the
University of Chicago Medical Center, Department of
Radiation and Cellular Oncology

Prostate Cancer: Improved Outcomes
Dose Level Advanced Stage
2.5-Year Local
Complication Rate
(Grade 2 Bleeding)
Control (Biopsy)
68 Gy 43%
70 Gy
76 Gy
81 Gy – 3D CRT
81 Gy - inverse planned (IMRT)
64%
73%
96%
>6%
6%
17%
10%
2%

IMRT - A Complex Process involving a team of physicians, physicists and radiation therapists (big shortage of physicists!!!) (see table next slide)
Patient
Immobilization
Structure
Segmentation
Planning
Plan Verification
Position
Verification target localization
Delivery
Treatment
Optimization
Treatment
Delivery and Verification

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

Image Guidance (PET/CT) allows to determine accurately position of the tumor
Tumor
Node #1
Tumor Tumor
Node #2

Bite-block Head
Holder
Aquaplast
Vacuum frame Breath Control
Spirometer
Newest development : systems which adjust for breathings while delivering beams. Use of lasers, ....

Treatment Delivery: Multileaf Collimator insures high transverse resolution

0.03 MU Dose Delivery
2.5 mm spatial longitudinal
5.0mm spatial lateral

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

Postulating a number of candidate radiation fields based on the planner’s experience; adjusting beam
Dose prescription is given first
A set of intensity-modulated external fields is generated through an parameters manually to create a optimization process better dose distribution.

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 a plan by a trial-and-error process.
This procedure won’t work for IMRT since there are too many unknowns (>2000 beamlet weights).

!
Conventional Treatment Planning
Forward Planning
!
!
40%
90%
80%
70%

?
IMRT Treatment Planning
Inverse Planning
?
80%
!
40%
90%
70%
?

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
C n

{ 1
M
 r
I ( r )[ D p
( r )

D n
( r )]
2
}
0 .
5 r denotes 3D elements of the body
D p
( r ) is the prescribed dose
I
D
( r n
( r ) is the computed dose at n th iteration
) is the weight (importance) for each organ the job of radiologist.

Cij -- dose contribution in voxel i from beamlet j in an open beam j wj
-- Weight for beamlet j i

i j

Total dose in voxel i
D i i
 j j


1
 j j

Or dose in any voxel in a more generic form
D


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

Source
Field
Volume total
Optimisation:

Field Direction.
 Beams directions.

Beams intersections with voxels.
 Lwe calculation.

Voxels ordering: (i,j,k)
 n .

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.
D required
( voxel )   beam w beam d ( beam , voxel )

Example of a treatment plan optimized with ANCOD++
Dose
Pixels along X
Y
X
X

Dose u.a
X

 DVH inside target
 DVH outside target

F ( W )   voxels



D voxel prescrite
  faisceaux w faisceau d ( beam , voxel )



2

Tomotherapy: A “revolution” in radiation therapy
Tomotherapy - slice therapy.
Two approaches currently developed: serial tomotherapy by 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 accelerator
Beam 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

Example: Conformal dose to breast & Internal
Mammary Chain (IMC)
Axial, Coronal, Saggital views of IMC/Breast delivery. Top row: Tomo Delivery,
Bottom row: Tangents, plus IMC photons and electrons (5 -field).

QuickTime™ and a
Cinepak decompress or are needed to s ee this pic ture.
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.