The Five R’s of Radiotherapy

Why do I need to get so many radiotherapy treatments? Why can’t I just have one radiation treatment and be done with all this radiotherapy already?

Many patients have questions about their radiotherapy treatments, which is good! The more you know about radiotherapy the better you understand our process and why we do things in certain ways to ensure you get the best treatment. One of the main questions patients often have is “why do I need so many treatments? Why can’t I just have one treatment? They ask this because often our radiotherapy treatments are split into fractions. Fractionation is where your Radiation treatment is split into many treatments, each held on separate days after each other. Radiation therapy treatments can have anywhere from 5 to 38 fractions.

I’m not a Radiation oncologist, but I do understand Radiobiology and why they prescribe fractionated treatments for patients. It’s to do with exploiting the biology of cells so that we can give enough dose to the tumor, and minimize the damage done to the healthy tissue surrounding it. This ensures the maximum effect on the tumor whilst minimizing side effects. The reason behind fractionation can be explained by the five R’s of radiobiology. These are taught to all radiation therapists, radiation oncologists and medical physicist in their training. The five R’s are the rationale behind fractionation of radiotherapy. The 5 R’s are Repair, Redistribution, Reoxygenation, Repopulations, and Radiosensitivity.

The First R is Repair

Repair is one of the primary reasons for fractionated radiotherapy. There are three types of damage to cells that ionizing radiation cause, as I will discuss in an upcoming post about DNA damage and repair. These are lethal damage-where the cell dies, sublethal damage-which can be repair, and potentially lethal damage-which can normally be repaired under certain conditions.

Now by splitting the radiation dose into smaller parts (fractionation) cells are allowed time to repair sublethal damage. Sounds alright, except we don’t want tumor/cancerous cells to repair at all, we want them to die. OK, here is where it becomes useful. The amount of damage repaired depends on the cells’ ability to recognize it has been damaged, then it will activate its repair pathways. The difference between healthy cells and tumor/cancer cells is that tumor cancer cells often have suppressed repair pathways. Or another way to say it is that tumor cells don’t always recognize they are being damaged and don’t repair themselves.

So by fractionating the dose of radiation we allow normal cells time to repair themselves before we give more dose. This limits the damage to normal cells while killing the tumor cells. Have a look at the figure below which visually show the effect of fractionation. With fractionation you can see that the healthy cells repair themselves, allowing more cells to survive. Without fractionation you can see that the number of surviving cells for healthy and tumor cells are roughly at the same level.

The number of surviving cells with time. Showing the difference between radiotherapy with fractionation and radiotherapy without fractionation

The Second R is Redistribution

Cells go through 4 phases in their life. This is known as the cell cycle. In these different phases their sensitivity to radiation is different. The phases the M phase, G1, S phase, and G2 phase. M is the mitosis phase, this is where the cell divides into two new cells. The G1 stage then follows, this is a gap stage. Cells that do not successfully divide die during this stage. The S phase is the phase where the cell synthesizes a copy of its DNA in preparation to split into two. This is then followed by another gap phase. Then finally the cell starts the M phase again.

Cells are the most sensitive to radiation when they are in G2 and M phases, after both sets of DNA have been created. Cells are the least sensitive in the S and G1 phase. More on why this is later. So the way in which fractionation benefits us is the time between radiation dose allow tumor cells to transition through the phases. A tumor cell in a low sensitivity phase for the first treatment will probably be in a higher sensitivity phase for the next treatment. And so on.

A simplified cell cycle diagram showing the 4 stages of a cells life

The Third R is Reoxygenation

Tumours are basically a bunch of cells invading a tissue without any sort of objective, they just multiply. When they grow like this they get to a point where oxygen from the blood can’t get to the cells in the center of the tumor. This is because the tumor has invaded the tissue to such an extent that no blood vessels get inside. The cells without oxygen go into a state where they don’t cycle through the phases described above. These cells without oxygen are in the G1 Phase, which makes them insensitive to the radiation treatment. If one treatment was given these cells would probably not dies.

Fractionation overcomes this by killing the tumor cells at the edge. This allows oxygen to flow to the inner tumor cells previously blocked by the outer tumor cells. Now the cells will have oxygen again they will start to go through the phase cycle again and hopefully the next radiation treatment will kill them. This again lets oxygen to more inner cells and so on.

The Fourth R is Repopulation

Repopulation is a tissue’s response to a decreasing number of cells. There is a delayed response between cell killing through radiation and the tissue repopulating the dead cells. This is different for different tissue types. On average it takes around 4 weeks for a tissue to start repopulating after radiation exposure.

Fractionation helps in certain cases where the normal tissues’ response time is shorter than the time to have all treatments. Say the normal tissue started repopulating in 4 weeks, and the total treatment time is 6 weeks. This means that in the last two weeks the normal tissue is starting to repopulate. This reduces side effects as the normal tissue as a whole is repairing itself to some degree.

But, repopulation can be a double edge sword. If the tumor cells start to repopulate before all the treatments have been delivered you might see an accelerated growth of the remaining tumor towards the end of the treatment. So there is a trade off between allowing the healthy tissue time to repopulate and allowing the tumor cell time to repopulate.

The Fifth and final R is Radiosensitivity

Radiosensitivity is a newer member of the R’s. It reminds us, that apart from Repair pathways, Redistribution of cells, Reoxygenation of malignant cells and Repopulation there is a difference in Radiosensitivity for different cell types. There are sensitive cell types. These are cells like stem cells, sperm and egg cells, intestinal cells and blood cells. Then there are cells that are not sensitive to radiation like neuron or brain cells, and tumor cells like melanomas. So why is there a difference? Generally speaking, you can say a cell is sensitive to radiation is the tissue it belongs to needs to repair itself often. I will explain this more in a later post. For now, that’s enough writing for one day.

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