While the number of particles in the beam decreases at it penetrates farther, we are more concerned about how the dose to the patient decreases. Since more particles will deliver a higher dose, they are related, but the relationship is more complicated than it appears. For the most part, DNA is not damaged by the beam particles directly, but by the particles with which they interact. For example, a photon beam with an energy in the range of about 1 to 20 megavolts is most likely to interact with an atom by a process called Compton scattering. This process transfers energy from a photon to an electron which can then interact with cells in the body and kill them. These electrons are mostly scattered forward (along the beam). When a photon beam enters a patient, the dose is not delivered right at the skin, but further in the body where the Compton scattered electrons, either directly or by creating free radicals, damage the DNA. This results in what is called skin sparing, where a high energy beam of radiation delivers less dose to the skin than it does to points deeper within the body. Note that this is a greatly simplified version of the true physics of the situation (even more so than usual), but gives the general flavor of what is going on.

So what does the dose delivered to a patient actually look like? We can get an idea by measuring the dose delivered to a tank of water known as a phantom. Dose measuring instruments known as ion chambers move within the tank and show us the dose distribution. (Obviously a patient is not a tank of water, but we can correct for that in our calculations.) This figure shows a curve of dose versus depth within the phantom for a 6 megavolt and an 18 megavolt beam. Note that the point of maximum dose (called dmax) is deeper for the 18 megavolt beam. This makes sense as the higher energy photons will give more energy to the scattered electrons and drive them deeper into the water. Also note that the higher energy beam delivers a higher dose as a percentage of the maximum dose than the lower energy beam. These curves are called depth-dose curves and are the basis for radiation treatment planning.

In the next post I will show how these depth dose curves are used to plan treatments, and why we need full-time dosimetrists to do it.

Once the beam is generated, it is collimated so that only photons travelling forward are let through. This beam is much more intense in the forward direction, so a filter is put in place to cool the beam down towards the center. After passing through this flattening filter, the beam profile is more uniform across its width. This is important since we do not want one side of the tumor to get less dose than another. Once we have a relatively flat beam to work with, we can begin to shape the field to the patient. Most linear accelerators have a pair of collimating “jaws”. These jaws are made of lead or tungsten, and are movable so that the field can be blocked to make it square or rectangular with sides up to 40 cm long (for a typical linac). These collimators are housed in the “head” of the linear accelerator.

The directions in which a linear accelerator can rotate.

The beam then exits the linac through a window. Further tools to shape the beam can be mounted to the outside of the window between the beam and the patient. One such device is a wedge, a physical wedge of metal that lowers the dose on one side of the field relative to the other. Another is a block, a layer of attenuating material that stops the beam in certain areas to shield normal tissue beneath it. These blocks are usually custom made for each patient to conform to the edges of the treatment volume. Usually the material used is called cerrobend or Wood’s metal. This is a lead alloy that has a very low melting point, only 70 degrees Celsius. This makes it very convenient to melt down and form.

The downside is that forming cerrobend blocks is very labor intensive, and for a busy clinic, making blocks is a full time job. In addition, any change that needs to be made during a patient’s treatment means that you have to start from scratch with a new block. Since lead is a hazardous material, making blocks is complicated from an occupational safety standpoint as well. For these reasons, the multi-leaf collimator or MLC was developed.

The leaves of a multi-leaf collimator

Shielding the eye from radiation using a block or mlc.

Conforming the beam to match the desired field is where the physics staff (physicists and dosimetrists) start to make the physician’s treatment plan a reality. It is where we work closest with the physician to make sure the right balance between tumor dose and normal tissue dose is struck. So what goes into that decision? My next post in this series will explore how the beam of radiation delivers the dose to the patient, and future posts will discuss how we use that information to create a treatment plan.

Image licensed under the Creative Commons Attribution ShareAlike 2.5 license from Vojtěch Hála.

The simplest device for creating X rays is the X ray tube. An X ray tube is simply a vacuum tube that has a filament on one end that emits electrons and an anode on the other end to collect them. A high voltage is placed between the filament or cathode and the anode to accelerate the electrons. The energy of the electrons is measured in electron volts. One electron volt is the energy an electron gets when it is accelerated by one volt. If you were to place a voltage of 1 kilovolt across an X ray tube, the electrons would have an energy of 1 kilo electron volt (or 1 keV). When the electrons hit the anode, bremsstrahlung photons are given off. These photons can have an energy up to the energy of the incident particles. Therefore, if 100 kilovolts were placed across the tube, the energy of the electrons would be 100 keV and the photons could have an energy of up to 100 keV. Usually, though, the peak of the spectrum is at an energy of about 1/3 of the incident energy.

Systems like X ray tubes work well for energies in the kilovolt range, but become large and cumbersome if used to generate photons in the megavolt range. Since photons with a higher energy can penetrate further into the patient to treat a deep seated tumor, other methods of generating radiation that could reach megavolt energies were developed. There are several types of accelerators that can generate photons with that high of an energy, but the one that is most often used is the linear accelerator. This figure shows a block diagram of a typical linear accelerator or linac.

A block diagram of a typical linac.

The linear accelerators in use today use microwaves to accelerate electrons. The waves are generated by a device called a magnetron (you have a smaller version of one in your microwave oven) or by a microwave amplifier called a klystron. The microwaves then travel through a waveguide into an accelerator tube. When electrons are injected into the accelerator tube from an electron gun, they can pick up energy from the waves and be accelerated. The accelerator tube can be manipulated to give different amounts of energy to the electrons and therefore different final energies for the beam. Very large accelerators like the Stanford Linear Accelerator Center can accelerate particles to energies of Giga electron volts. Medical accelerators are more compact and generate electron beams with energies in the Mega electron volt (MeV) range. A bending magnet then steers the beam into a metal target to generate X-rays. The bremsstrahlung process is very inefficient. Only about one tenth of a percent of the electron beam energy is converted into usable X rays. Most of the rest is dissipated in heat in the target. Therefore, the target must be made of something that is very heat resistant like tungsten and is usually water cooled. Once the X rays are generated, the beam is collimated and shaped in the treatment head.

Whether the X rays are generated by a linear accelerator, an X ray tube or another type of source, the energy of the beam is described by the energy of the incident electron beam. So the X rays resulting from a beam of electrons with an energy of 1 MeV will be described as a 1 megavolt (MV) beam. This is even though as discussed above, very few of the X ray photons will have an energy close to that of the incident electrons. It just provides a convenient shorthand for describing the shape of the X ray spectrum. In future posts I will describe X ray beams using terminology like 6 MV or 18 MV. When I talk about a 6 MV beam, I mean the beam of photons with an X ray spectrum that results from accelerating electrons with a voltage of 6 MV.

You can also get rid of the target and allow the electron beam to treat the patient directly. Electrons have advantages over photons for some types of treatments. Electrons have a much shorter range and are therefore more desirable for treatments that are very close to the skin. It’s important to remember though that by removing the target you get rid of the inefficiency of the bremsstrahlung process. Therefore the electron beam current will have to be lowered by a factor of 1000 (since the X-ray production of the target is 0.1% efficient) to have roughly the same dose as an X-ray beam. Electron beams are described in units of MeV, as in 6 MeV. They can also be described with just the letter E as in 6E (as opposed to X for photons as in 6X). The 6 in 6E or 6X is understood to mean 6 MeV or 6 MV.

Once the X rays have been generated, they have to be shaped to conform to the area that needs to be treated. In the next post I will describe the various devices we use to shape the beam to provide the optimal treatment for an individual patient.

Of course, there is a solid biological reason for extending the treatment over such a long period of time. In my last post, I wrote about the need to balance killing the tumor with damaging the surrounding normal tissue. In this post I will show how using fractionation, or dividing the total dose into a number of smaller doses, can help improve what is referred to as the therapeutic ratio, the chance that the tumor will be killed versus the chance of a normal tissue complication.

I’ve tried to keep the discussion so far at a high level, but the easiest way to understand these concepts is visually so I’m going to use some figures to help illuminate my points. An important point to keep in mind is that the following discussion is a simplified model based on experiments done with cells in a lab. Still, to a certain extent, the basic features correspond to what we see clinically.

More normal tissue cells than tumor cells survive

One thing to notice about the curves is that at low doses the curve is almost a straight line, while at higher doses it bends more sharply. Suppose we were to give the tumor a small dose, one that stayed within the linear part of the curve, and then wait until sublethal DNA damage had been repaired. Each small dose would then start back along the cell survival curve from zero. We could continue to give these small doses until we had achieved the same probability of killing the tumor as before.

Fractionating the dose improves the therapeutic ratio

If we massage the statistics a little bit more, we can generate curves of tumor control or side effect probability versus total dose for a single dose and a series of small doses. The red curve shows the probability for tumor control while the blue curve shows the probability for normal tissue complications. If we were to give the dose indicated by the vertical line, there would be a small chance of normal tissue complications, but a much greater chance of killing the tumor. The ratio between the two probabilities is called the therapeutic ratio. If we could somehow shift the tumor curve to the left (or towards less dose), the chance of tumor control would increase dramatically while the chance of side effects would remain the same. This is shown in the bottom figure. Conversely, if we could shift the normal tissue curve to the right (towards higher dose) and increase the dose to maintain the same complication rate, then we would also have a greater chance of tumor control. When we fractionate the dose, both curves move towards higher dose, but the normal tissue curve moves further than the tumor curve. In this way we can improve the therapeutic ratio.

Improving the therapeutic ratio is the central issue in radiation therapy. Fractionation is one way to do it. Determining fractionation schemes is difficult, however. Cell survival curves can be measured in a laboratory using cultured cells, but cells in the body react differently to radiation than cells in a Petri dish. Tissue tolerance can be tested in animals, but applying the data to humans is problematic. The best way to test fractionation schemes is to conduct a clinical trial, looking at the rate of complications and the rate of tumor control across a large number of patients. Clinical trials are time consuming and expensive and are well beyond the capabilities of small clinics. In practice, most clinics use well established schemes, using fractions of 1.8 to 2 Gray each weekday with a 2 day break on the weekend. There are other schemes such as treating a patient twice a day or using higher doses per fraction, but these are specific to the type of tumor and staging of the patient.

Another way of improving the therapeutic ratio is to decrease the amount of dose that normal tissue receives relative to the tumor. This will reduce the normal tissue complication rate without sacrificing tumor control. In practice, this is where most clinics spend their effort. The process is called treatment planning, and all clinics have at least one person called a dosimetrist who spends the majority of their time trying to accomplish this goal. There are a lot of different things a dosimetrist can try, but explaining them involves some knowledge of how the dose of radiation is delivered to the patient. So in the next few posts in this series, I will give an overview of how a linear accelerator works, and how we can use it to shape the distribution of dose in a patient.

References
All of the figures in this post are inspired by figures in the following references.
Hall, E and Giaccia, A (2005) Radiobiology for the Radiologist, Lippincott Williams and Wilkins
Perez, C et.al. (2007) Principles and Practice of Radiation Oncology, Lippincott Williams and Wilkins

Many types of cells in your body constantly divide in order to replace cells that have died or been sloughed off. However, several mechanisms are in place to keep these cells from growing out of control. Some cells have internal programming that kills them once they have divided a certain number of times. There are also intercellular signals that prevent cells from growing beyond the extent of their proper environment. Cancer cells have lost these controls. They can divide an indefinite number of times and expand throughout the body. Not all cells in a tumor have this ability; the ones that do are called clonogens. A single clonogen can potentially grow into a life threatening tumor.

In order to control a tumor, we must kill all the clonogens within it. The problem is that a high enough dose of radiation to kill every clonogen will also kill normal tissue cells surrounding the tumor. It is virtually impossible to give a curative dose to a tumor without the surrounding tissue also receiving a dose as high or higher. If enough normal tissue cells are killed, the patient may experience severe and possible life threatening effects. There is a saving grace, though. Radiation therapy takes advantage of a major difference between tumor and normal tissue cells, though: tumor cells divide much more rapidly than normal tissue cells. This makes sense as the reason a tumor endangers the patients’ life is its uncontrolled and rapid growth rate.

To understand why the rate of cell division makes such a big difference, we need to know exactly how radiation kills cells. Ionizing radiation creates free radicals that can react with the DNA in cells and damage it by breaking the strands of the double helix. Radiation can also interact with DNA directly and damage it. Regardless of how DNA damage occurs, there are a few possible outcomes. The cell may recognize the DNA damage and kill itself in a process called apoptosis, i.e. programmed cell death. Or, when the next cell division occurs, if the cell’s chromosomes are too damaged then the cell will spontaneously die. However, if there is enough time before the next cell division then the cell may be able to repair its DNA and therefore survive. This is the crucial distinction between normal cells and tumor cells; tumor cells have less time to repair DNA before cell division occurs, and are therefore more likely to be killed by ionizing radiation.

There is yet another wrinkle that complicates the treatment of tumors with radiation. DNA is a double helix and has two strands. If only one strand is broken, the cell is more likely to be able to repair the DNA. If both strands are broken (and both breaks are close to one another), the cell will possibly be unable to heal. Interactions of ionizing radiation are what is called a stochastic, or random, process. Every particle of incident radiation has a certain probability of causing DNA damage. The higher the dose, the more likely it is that a strand of a cell’s DNA will be damaged and the more likely the cell will die.

Now we are presented with a conundrum. We want to give the tumor a high enough dose to kill all of the clonogens, but not such a high dose that normal tissue cells are unable to repair themselves. If all of the dose is given in a single treatment, it is very difficult to meet both of these objectives (unless advanced patient positioning techniques are used). However, we can accomplish both by spreading the total dose out over a number of treatments. This is called fractionation, and it will be the subject of my next post in this series.

References
Hall, E and Giaccia, A (2005) Radiobiology for the Radiologist, Lippincott Williams and Wilkins
Perez, C et.al. (2007) Principles and Practice of Radiation Oncology, Lippincott Williams and Wilkins