Can Electrons Cure Cancer?

Can Electrons Cure Cancer?

What are Electrons?

Electrons are the tiny particles in atoms which orbit around the nucleus. Electrons can, however, also be free, meaning they are not attached to any atom. These subatomic particles are negatively charged and fundamental, meaning they cannot be broken down into anything smaller. In fact, electrons are so small that if the proton in a hydrogen atom, that is, the nucleus, were the size of 

a basketball, the electron would be the size of a golf ball. Moreover, it would be orbiting the basketball at a distance of 8 km! It might be strange to think that something so tiny, and which surrounds us wherever we are without being visible to us, could help us fight cancer. It is, after all, many times smaller than the size of a cell. However, thanks to the creativity of scientists, the idea might not be such an alien one after all.

Why this Strange Idea?

Cancer is a global burden. About 30-40% of people will develop cancer during their lifetimes. In 2020 alone, it is estimated that around 19.3 million cancer cases occurred, with 10.0 million cancer deaths. By 2040 the global cancer burden is expected to have seen a 47% rise from 2020, with 28.4 million cases that year. It is therefore not surprising that the race to improve the treatment of cancer, and, where possible, finding a cure, is more pressing than ever. The battle against cancer engages people and scientists from every field, including physicists. Their approaches include for example radiotherapy, hadron therapy and proton therapy. Here, we will briefly present a relatively novel treatment strategy physicists are developing for cancer, namely the use of electrons. This approach is itself divided, consisting of methods looking, for example, both at the use of high- and low-energy electrons. Both types will be outlined here. 

What is External Beam Radiation Therapy? 

External beam radiation generally involves focusing an ionised radiation source at a malignant part of the body. The goal of this treatment is to impart maximum damage, by means of radiation, to cancer while sparing any surrounding healthy tissue. Cancer treatments involving external beam radiation typically use either photons, protons or electrons. External Beam Electron Radiation therapy uses beams of these freed electrons, which were previously mentioned. Low energy electron beams are specifically used for superficial tumours, since they cannot travel deep into the skin. Cancers, for which treatment may utilise electron beam therapy, include skin, lip and neck cancers. Electron beam therapy differs from the conventional photon beam therapy because photon radiation can penetrate deep into the skin, while sparing surface tissue, but low energy electron beams cannot. Electron beam therapy damages tumour cells by causing DNA double strand breaks or cell membrane damage. In contrast, high energy electron beams can penetrate deep into the skin, but they become less accurate in targeting their treatment area when doing so. Therefore, mainly low-energy electrons have been used in medical treatment so far.

Low Energy Electrons

Low-energy electrons appear in the majority of physical and chemical phenomena underlying radiation, playing a central role in determining the effects of ionising radiation. Hence their potential use in the battle against cancer is evidently worth investigating, seeing as one of the main treatment forms until the present day involves radiation therapy (in addition to chemotherapy, immunotherapy and surgery). Looking at the production of low-energy electrons in ionising radiation events is essential to understanding their potential. Although initially studied in water, the research carried out thus far on low-energy electrons in liquid is nonetheless seen as helpful due to the fact that tumour-bearing tissues often have a significantly higher water content than the normal tissues from which they have been derived.

How Are Electrons with Low Energy Produced?
Ionising radiation is radiation which carries enough energy to knock an electron out of an atom, in a sense “freeing” it. Ionising radiation passing through molecular media transfers energy to the molecular electrons present. This is through discrete collisions and the result is the excitation of the electrons. In turn, this leads to either the production of an excited state of the molecule or complete ionisation, meaning the liberation of the electron. This transfer of energy from the radiation particle to a molecular electron is a stochastic event, which can be described using collision cross-sections and its radiation track structure modelled with Monte Carlo methods. Put simply, scientists have found a way to mathematically model the process of ionisation leading to the creation of  secondary, or “daughter” electrons. These are the electrons with low energy which are potentially useful in treating cancer tumours. The energy of the primary particle is reduced in a collision and any daughter, low-energy electron can be followed between collisions thanks to the modelling.

Amongst other things, the models and simulations developed by scientists can determine the energy distribution of daughter electrons when attenuated to sub-excitation level, defined as being less than 25eV. “eV” stands for “electron volt” and is a unit of the energy of an electron. It is found that the ionisation of liquid water occurs at approximately 6.6 eV yielding a most probable secondary electron energy of <15eV .

After liberation, these secondary electrons undergo their own attenuation: they transfer energy to molecular electrons, leading to ionisation, and excitation, until an energy of approximately 25eV is obtained. The below figure shows the energy of the sub-excitation electrons produced by a primary electron with an energy of 1,000,000 eV (this is also known as 1 mega eV, or 1 MeV). A quite large part of these resulting low-energy electrons (27%) are produced with an energy between 0eV and 1eV. The remaining electrons have an energy in the range of 1eV to 25eV. The average energy is around 9eV. Hence a value of approximately 9eV is the most probable secondary electron energy as a result of ionising radiation in liquid water.

Low-energy electrons can also be produced using the Auger Effect. This is when a vacancy in a k-shell electron is filled by an electron from a higher shell with lower binding energy. The energy difference of this transmission is either emitted as a characteristic x-ray, or it is transferred to another electron. This electron is then ejected, leaving two electron vacancies in a shell. This induces other electron ejections. 

The amount of  low-energy, ‘‘daughter’’ electrons at each energy, produced in liquid
water by 1,000,000 eV primary electrons.

Why this is Only Possible in Recent Times

In the early and mid 20th century, electrons had been studied by physicists in such a way that their movements could be predicted in an electric field. However, lack of computer power made it difficult to apply this research in a medical setting. Since 1975, there have been groundbreaking discoveries in the area of electron transport, such as the Monte Carlo method. This is a method which allows a computer to accurately predict the motions of electrons while being used in electron beam therapy. This discovery has allowed us to employ electrons in medical treatments. 

Intra-operative Electron Therapy

People first had the idea of using electron beams to treat cancer in Japan in the 1960s. Before that, doctors could only use x-ray beams, which were too weak and imprecise in comparison. It has since really taken off because when electrons are used to get rid of cancer, it’s normally gone for good! When the doctors have opened up the patient in surgery, they apply the electron beam directly to the cancer, which kills the cancer cells. Using the beam makes the surgery much easier for the doctor too! This treatment method is really popular with patients also, because it’s really good at only harming the cancerous cells, and leaving the healthy skin safe and sound. It’s so accurate that the doctors hail its precision regularly. Intra-operative means that the process takes place during the operations, so the physician actually gets to see exactly where the problem area is, and how to fix it. Doctors and scientists agree that the intra-operative method is one of the best ways of using electrons to treat cancer, and its high success rate means that patients can go back to living a normal life without having to worry about their cancer returning.

One of the leading causes of death in the United States is pancreatic cancer. A study of medical records from Massachusetts General Hospital from 1978 to 2010 found that when doctors manage to catch cancer early on, intra-operative radiotherapy can eliminate the cancer quite quickly, without too much invasive surgery.

Similarly, scientists in Italy have found that over the course of 7 years, intra-operative radiotherapy has managed to help 99 out of 100 people beat their breast cancer for good! Such strong results from these studies have meant that in the past 10 years, way more doctors have started using this method early on to catch cancer fast and help people go back to living their normal lives.

Two of the most difficult cancers to treat are cancers in the head and the neck. Head and neck cancers often also have a very high rate of recurrence. However, using the electron beam on this kind of cancer during surgery really helps the patient heal much quicker than they normally would, because the electrons are really good at stopping any remaining cancer cells from growing back.

Using Electrons to Cure Cancer in the Real World

This all sounds great, but is any of this science actually used in practise? Surprisingly yes! Admittedly, low energy electron radiotherapy is not the most popular form of cancer treatment in use, but it has been in use for quite some time. Low energy electron beams have been featured in radiotherapy wards since as early as the 1940s and really came into fruition in the 1970s when the linear accelerators became more commercially available. Today, low energy electron beams are used in some hospitals around the world and it is also the subject of many clinical trials which aim to improve the technology and make it more patient friendly. To prove the point, at the University of Texas MD Anderson Cancer Centre(MDACC), they estimate the 15% of cancer patients receive low energy electron radiotherapy as part of their treatment. At the MDACC, low energy electrons are used to treat cancer sites that are near to the surface of the skin such as the scalp, breast and tongue. The technology is most useful in a procedure that is known as total skin electron beam therapy. This involves the electron beam treating the entire surface of the skin and is currently being used in NHS hospitals.

As mentioned before, as with any medical technology there are ongoing studies and trials to try and improve the effectiveness of the technology. This is no different with low energy electron beam radiotherapy. There is currently a clinical trial taking place in the University Hospital Heidelberg that explores the effects of an intra-operative electron therapy on low-risk early breast cancer patients. One of the problems with electron radiotherapy, and indeed all radiotherapy, is that after the treatment, up to 80% of patients are left with symptoms of fatigue. This trial aims to use electron therapy during a tumour removal operation and only on small parts of the breast, in the hope that the procedure will still be effective but also leave the patient feeling less fatigued. Up to now (May 2021), 48 patients have been included in the trial and the estimated primary completion date is September 2021.

Using Auger Electrons in Clinical and Preclinical Trials

As we have talked about above, it is also possible to produce electron beams by the Auger effect. These are really low energy electrons and could be really effective for the treatment of cancer cells. These electrons can cause damage to the DNA of cancer cells by something called “water radiolysis”, this is the decomposition of water molecules due to radiation. Also the Auger electrons can damage the membrane of the cancer cell. There are lots of interesting clinical and preclinical trials involving these electrons, a few of which will be described below.

The most famous preclinical trial using Auger electrons was conducted by Kassis and Adelstien. In this trial, a special form of Auger electrons were incorporated directly into the DNA of the cancer cell. This was found to cause something called DNA double strand-breaks resulting in the conclusion that auger electrons are very cytotoxic (harmful to cells). This is an encouraging result as it means that if the auger electrons can be targeted at the correct cells, they are likely to destroy them. Another preclinical trial conducted by Chan et al, aimed to investigate how cells from a breed of Chinese hamster reacted when exposed to a type of Auger electrons. The result of this trial was that the electrons were extremely cytotoxic and most of the hamster cells were destroyed. It has been found that these early trials of DNA targeted auger electron radiotherapy in mammalian cells shows that the auger electrons are highly cytotoxic when emitted close to DNA. These results are encouraging for the future of this form of radiotherapy!

In comparison to pre-clinical trials of auger electron therapy, there are relatively few examples of clinical trials involving the use of auger electrons. However, there have been clinical studies performed over 20 years ago. For example, a trial performed by Macapinlac et al has investigated the size of dose  and safety in four patients with colorectal cancer using extremely low doses. It was found that no tumour responses were detected (however none were expected due to the low dose), but more importantly, no side effects or toxicity was detected. Another study performed by Krenning et al. involved 30 patients, each administered 14 doses with each dose at 6-7 GBq. The unit GBq is called a Giga Becquerel and is commonly used to describe the strength of a dose. Among 21 patients who completed the trial and received a cumulative amount greater than 21 GBq, 6 patients showed a reduction in tumour size and all patients reported no noticeable side effects.

Future Changes in the Practice of Electron Therapy Resulting from Challenges to its Utilisation & from Potential Future Technology

As mentioned above, unfortunately electron therapy is not the most popular form of cancer treatment available. There is not sufficient technology in place to take advantage of electron therapy, since it is not in demand from manufacturers. Another possible reason for its lack of popularity is that radiographers & oncologists are not extensively educated in the topic. Additionally, a treatment called tomotherapy  has similar capabilities as electron beam therapy since it uses intensity modulated radiation therapy (IMRT), which allows the avoidance of normal tissue. This is achieved by taking a 3D photo of the tumour prior to radiation & then imparting the highest dose of radiation on to various parts of the body, causing minimal damage to health nearby tissue.Although electron beam therapy is in use in some hospitals, it is likely that its use will only become more widespread following improvements to  dose homogeneity in tissue or creating a more efficient beam delivery system.

While there is currently no clinical trials taking place using Auger electrons as a form of treatment, trials from the past give reason to be optimistic about the future deployment of this technology in the field. Further preclinical testing combined with improved strategies to improve the delivery of Auger electrons to the nucleus could see an uptake in this form of radiotherapy.

High Energy Electrons

At the other end of the spectrum, technologies behind high-energy physics have historically contributed to great advances in the field of medicine. Treatment of tumours is complicated by the need to limit, or preferably avoid, doses to surrounding normal tissue. The use of high-energy electrons for the purpose of improving differentiation between malignant and normal tissue is a technique which scientists only started to turn their attention to in 2014. The technique is still being developed. Electrons with an energy of around 100 MeV penetrate many tens of centimetres of tissues and can thus reach deep-seated tumours. 

How Are Electrons with High Energy Produced?
Useful for the creation of such energetic electrons is the accelerator technology developed for the “CLIC electron-positron collider”. CLIC stands for the Compact Linear Collider and is being constructed at the research centre CERN, in Geneva. It is a large piece of machinery which collides electrons with their antiparticles, i.e. positrons, at energies which range from a few hundred GeV (giga eV, 1,000,000,000 eV!) to even a few TeV (tera eV, 1,000,000,000,000 eV – very energetic!). CLIC, whose mechanism is illustrated in the below figure, provides high levels of electron-beam polarisation at a range of high energy values. In fact, the CLIC project is capable of accelerating electrons at energies as high as 3 TeV!

Simplified schematic of the “drive beam” and “main beam” particles travelling in the
CLIC accelerator complex at CERN in Geneva.

In a linear accelerator such as CLIC the full energy from collisions must be delivered to the particles in a single passage through the accelerator. Hence, the accelerator must be equipped with several acceleration structures distributed along its length. CLIC is built to be operated in three stages with increasing collision energy and luminosity (brightness). Two-beam acceleration technology achieves a high acceleration of the particles per metre. It is radio-frequency pulses which accelerate the main beam, and these pulses are generated by decelerating a second, high-intensity electron drive beam in dedicated structures. Synchronisation of the arrival time of the two beam bunches is very important to generate electrons with the desired energy.

A scientist working on the CLIC  at CERN with the hope of generating high-energy
electrons which are effective in the treatment of cancer.

Using High Energy Electrons to Cure Cancer in the Real World

While low energy electron radiotherapy is useful for the treatment of sites that are within a few centimetres of the surface, there is potential for use of high energy electrons in treating deeper tumours. The issue here arises when we consider that the deep tumour must be treated without irradiating the surrounding healthy tissue. This proves to be a difficult task when dealing with electrons that have energy in excess of 100 Mev.

That being said, a paper published by Kokurewicz et al in 2019, details that increased inertia of high energy electrons due to relativistic effects can reduce scattering and enable its use in treatment of deep tumours. The paper focuses on Monte-Carlo simulations of high energy electron beams in water and concludes that the dose can be concentrated into a small volumetric element. This means that the surrounding tissue receives a dose that is spread over a larger volume. This is a promising result for high energy electron radiotherapy as it means that the technology can be used to treat tumours without irradiating surrounding, non-carcinogenic tissue.(Kokurewicz et al., 2019). In addition to this, studies are also being conducted to determine the dosimetry properties of high energy electron beams using Monte-Carlo methods. 

The current extent of this technology is only in the form of research and optimisation with no preclinical or clinical trials presently underway. In contrast to low energy electron radiotherapy however, this is very much an emerging technology and given more research we could very well see preclinical and even clinical high energy electron treatment trials in the future.

Conclusion

Doctors and scientists are always looking for new innovative ways to treat cancer. Radiotherapy has long been established as a common way to treat cancer patients, however recently the use of electrons has gained a foothold in the medical community. With current methods, electrons cannot travel very far through body tissues and the side effects have been severe enough to limit their use. Therefore, their use is limited to tumours on the skin or near the surface of the body, however use of electron radiotherapy during surgery is currently being studied, which would enable physicians to apply electrons to cancerous cells with surgical precision. The electron radiation works by making small breaks in the DNA inside cells. These breaks keep cancer cells from growing and dividing and cause them to die. Nearby normal cells may be affected by radiation, but most recover and go back to working the way they should. 

There are certain cancers that are more sensitive to radiation than others. Radiation may be used by itself in these cases in order to shrink or eradicate the cancer.  However in many other cases, chemotherapy or anti-cancer drugs may be required also. Electron radiotherapy has emerged as one of the most promising cancer treatment methods. Future and current research into the practice is a prominent topic within the field of medical physics.Potentially less invasive ways to treat cancer using precise applications of electron radiation will provide better outcomes for patients, and could provide effective treatments against cancer that avoids the negative physiological effects of chemotherapy. Further discoveries and research in both the realms of physics and medicine are highly anticipated as developing breakthrough cancer treatments could help humanity to turn the tide in the battle against cancer.