Radiotherapy Charged With New Energy

"Different types of tumours vary in how sensitive they are to the stress that radiotherapy causes. These are cancer types where radiation is often curative," says Mattias Hedman , head of radiotherapy at Karolinska University Hospital in Solna and researcher at the Department of Oncology-Pathology at Karolinska Institutet.

Sometimes radiation is used to shrink a tumour before surgery ‒ or it is done after surgery to ensure that no cancer cells remain outside the removed tumour. In some cases, this is done for breast cancer, with the aim of reducing the risk of any remaining cancer cells starting to grow again. It can also be given palliatively to shrink painful metastases, for example, in the skeleton.

In short ‒ radiotherapy can be used for many different cancer diagnoses, at various stages of the disease, and with different purposes. The treatment is considered to contribute to a cure in about one-third of cancer cases.

"It is a very effective and flexible treatment that is underutilised from a global perspective," says Mattias Hedman.

Sweden has a proud history in this field. For example, what was likely the world's first curative radiotherapy was administered in Stockholm in 1899. It was reported that a woman had a skin tumour on the tip of her nose healed. During the first decade of the 20th century, Swedish doctors gained international recognition for successfully treating cervical cancer with radium applied locally inside the vagina.

Negative trend has been turned around

Swedish radiotherapy was world-leadingfor much of the 20th century and was at the forefront in Europe at the turn of the 21st century.

However, in recent decades, the tone has changed. Media reports have focused on long waiting times, staff shortages and an inadequate machine park.

About a decade ago, the Swedish Radiation Safety Authority described how Swedish research in the field had fallen behind comparable countries such as the United Kingdom and the Netherlands. The report also described a decline in funding for radiotherapy research, unclear whether it was due to fewer applications or a lower approval rate.

Following this cold shower of a status report, the country's oncology department heads appointed an expert group that produced a new report. It provides some explanations. One of them is that in countries like Denmark, the Netherlands and the United Kingdom, , there have been grants specifically targeted at radiotherapy research. Furthermore, it mentions a competitive situation within oncology, where the same doctors handle both chemotherapy and radiotherapy. Young researchers have then been absorbed into medical oncology, which has drained radiation oncology of competence, according to the report.

The situation in several other Nordic countries is described as equally bleak.

So, what has happened since then?

Quite a lot, says Mattias Hedman, who himself worked on one of the above-mentioned reports.

"Those of us who are active in the field have managed to organise ourselves and gather strength. I would say that we are in a positive trend where radiotherapy has become more attractive to work with," he says.

Here are some examples:

In 2021, the Swedish Cancer Society awarded SEK 65 million in a targeted initiative towards radiotherapy research. Grants were also awarded in 2022 and 2023.

The Government has asked the Medical Products Agency to review the national need for radiotherapy machines, called linear accelerators. The review is to be presented at the end of January 2025.

A new two-year programme, where the five Nordic countries collaborate to train their oncologists, has started. The first 30 participants will complete parts of the training in their home countries and other parts on-site in their neighbouring Nordic countries, with the intention of building networks and strengthening the profession.

- There is a momentum and focus in the field, and new studies are underway," says Mattias Hedman, who is also on the board of the recently founded Swedish Society for Radiation Oncology, where doctors, nurses and hospital physicists collaborate on issues in the field.

Seeking biomarkers for radiation sensitivity

Part of his own research involves finding biomarkers for radiation sensitivity. In this project, 550 women have provided blood samples before and after radiotherapy for breast cancer. In the samples, the researchers are looking for known inflammation markers and a genetic alteration that seems relevant to radiation sensitivity.

"We want to investigate whether the combination of high inflammation markers and this genetic alteration can predict more severe skin side effects. If it turns out to be a marker that makes it possible to predict radiation sensitivity, we can tailor information about the treatment even before it starts. Then a radiation-sensitive patient could receive support and care and have a better chance of completing their treatment," says Mattias Hedman.

The skin can react differently to radiation. In many cases, the skin is completely unaffected, while others may experience redness. Some may have peeling skin or even exuding wounds.

"In breast cancer, patients may have more difficulty tolerating severe skin reactions when we give what we usually call recurrence-preventive radiation, where the tumour has already been surgically removed. But if it is, , for example, a head and neck tumour, the patient often accepts more wounds, because then the radiation is the curative treatment," says Mattias Hedman.

The hope is that this study on breast cancer patients will evaluate biomarkers that can be used to predict radiation sensitivity. This knowledge can also be valuable for patients undergoing radiotherapy for other cancers.

Severe fatigue is also common in connection with radiotherapy. This is probably because the radiation causes inflammation in the body, whichin itself is tiring.

During treatment, tissue near the tumour can also be affected. In head and neck cancer, the mucous membranes in the mouth and throat can be damaged, making it painful and difficult to eat. In abdominal or pelvic cancer, radiotherapy can cause nausea or diarrhoea.

These early side effects are usually temporary.

More troublesome are the so-called late complications, or late effects, which can appear several years after radiotherapy. They are often difficult to address because the radiotherapy has already completed, so the dose cannot be adjusted.

Late damage is due to healthy cells being impaired in their ability to divide. Other functional abilities may remain intact, so the tissue continues to do its job after radiotherapy ‒ until the cells have aged. Then they cannot replace themselves, and the tissue loses its function.

Analysing radiation doses and side effects

"For example, someone might experience reduced saliva production, leading to discomfort and difficulty eating. Or a man might have urinary or faecal incontinence after radiation for prostate cancers. These can be quite serious side effects, but they are rare, I want to emphasise that. We do everything we can to plan the doses so that the surrounding tissue is spared," says medical physicist Eva Onjukka , who researches at the Department of Oncology-Pathology at Karolinska Institutet.

The risk of side effects is one reason why radiotherapy is given in fractions, that is, over several sessions. Healthy cells can repair DNA damage and recover, but these functions are impaired in the cancer cells. With repeated radiation, they therefore accumulate damage. From a treatment perspective, the so-called double-strand breaks are preferred, where both strands of the DNA helix are severed.

To avoid side effects, a lot of effort is put into calculating exactly how each tumour should be irradiated. A concrete example: if two lung tumours are the same size and otherwise similar, they probably need the same radiation dose. But to acheive this while sparing the surrounding tissue, the beams may need to enter from different angles with different strengths. The tissue that the beam pass through is at risk of damage.

"If a lung tumour is near the spinal canal, we really do not want to damage the spinal cord. Then we might choose to go in with a slightly higher dose through the lung instead. If the tumour is in another location, we might choose to go in with a lower dose through the lung to spare healthy lung tissue. These assessments are made on an individual basis for each patient," says Eva Onjukka.

Additionally, adjustments are made before each treatment session. New 3D images of the tumour, which may have shrunk or changed position, are taken. These new images help make adjustments, where the patient's position is fine-tuned to the daily anatomy.

All this creates great variation in the treatments given. One hundred patients who have received exactly the same radiation dose for, for example, a tumour in the lung, may have received that dose distributed in one hundred different ways. This makes it difficult to draw conclusions about the relationship between the radiation dose and late complications.

This is exactly what Eva Onjukka is researching, funded by one of the targeted grants from the Swedish Cancer Society.

"We need to move away from thinking that we have given a certain dose to a certain patient. Instead, we need to consider the full distribution of the delivered dose. With that approach, new ways to analyse the effects are needed," she says.

The mathematical models enabling this analytical method were adopted by Eva Onjukka from a previous international collaboration. Now, she will use them to analyse late complications from radiotherapy in head and neck cancer. More specifically, she will investigate how swallowing can be affected.

To find out, she will examine data from a quality register of head and neck cancer treated in Stockholm. The register contains information on various late effects experienced by the patients, such as severe swallowing difficulties. This side effect is rare, but for the two to three percent of patients affected, it is very challenging to live with.

Swallowing is quite a complex process that requires both the tongue and throat to function properly. "I want to see where in the anatomy the patients who have had problems have received a high radiation dose. And I will investigate this with regard to how the radiation was directed at the tumour in each individual case," she says.

Lithium can alleviate late complications

Today, about 300 children per year are diagnosed with cancer. Approximately one-third will develop some type of brain tumour, and just under half of them will receive radiation to the brain. This can lead to late complications, such as problems with learning, memory, concentration, and processing speed. All of these can cause difficulties at school and later in the workplace or in social settings.

"A typical situation that can be difficult is participating in group conversations. You are expected to listen, associate, and respond, all at high speed. If processing speed is reduced, which is very common after brain radiation, this interaction does not flow smoothly. And then these children can be excluded," says paediatric oncologist Klas Blomgren , who researches at the Department of Women's and Children's Health at Karolinska Institutet.

Research is ongoing into how the substance lithium can be used to alleviate these late complications. Lithium is already known to protect the nervous system and is used to treat bipolar disorder, even in children.

In studies with mice, lithium has reduced memory and learning problems that appeared after radiotherapy. The effect has been noticeable even when the lithium was given quite a long time after the damage occurred. The results have been so promising that the researchers are now moving forward to test the drug on children.

The recently launched study includes 84 children who have completed treatment for a brain tumour. They will be randomly assigned to receive lithium or placebo for six months. Various cognitive abilities will then be measured for up to five years after the lithium treatment is completed.

In this study, children whose cancer treatment (and thus radiotherapy) was completed up to seven years ago are included. However, the researchers believe that lithium may provide better protective effects if given fairly soon after radiotherapy, perhaps even while the treatment still is ongoing. Such a study is planned, but first, the researchers needed to ensure that lithium does not also benefit cancer cells. Therefore, mice with brain tumours were given lithium during ongoing radiotherapy.

It gave a surprising result.

The tumour shrank more than expected.

"Lithium has antitumour effects, but they are not particularly well described in the scientific literature," says Klas Blomgren.

In the long term, he wants to start a study where lithium is tested as part of the tumour-fighting treatment.

"Perhaps It will then be possible to reduce the radiation dose. That would also decrease the occurence of late complications," says Klas Blomgren.

Targeted radiopharmaceuticals may work against metastases

In conventional radiotherapy, which is administered via an external radiation source such as a radiotherapy machine, the goal is to direct the beams as precisely as possible at a small, defined area. This could be a single tumour or metastasis, or a chest wall after surgery for breast cancer. However, this poses a limitation when the cancer has spread throughout the body.

Targeted radioactive drugs are an attempt to circumvent this limitation. They can treat cancer cells in many places in the body simultaneously ‒ precisely because they are targeted and reach the tumours via the bloodstream.

One person developing such drugs is pharmacist Thuy Tran , who is an associate professor and research group leader at the Department of Oncology-Pathology at Karolinska Institutet. She explains the principle as follows: radionuclides, small amounts of a radioactive substance, are attached to molecules that fit exactly on the surface of specific cancer cells. After infusion, these molecules will move through the bloodstream until they reach the cancer cells. Then they stick there, along with the radionuclide.

At this point, the patient can be examined with a PET scanner. Tumours and metastases throughout the body will then be revealed.

"It is possible to detect small, disseminated metastases, sometimes long before they cause any symptoms," explains Thuy Tran.

In the next step, the patient receives a new infusion, again with targeted drugs, but with a different radionuclide. This will also attach to the cancer cells but emit radiation that damages them. In this way, it is possible to treat disseminated metastases, which may be located in several places in the skeleton or in the liver and lungs. This is called theranostics - therapy and diagnostics with the same method.

The research field is considered promising. Recently, the Theranostics Trial Centre, a collaboration between Karolinska University Hospital and Karolinska Institutet, was set up to bring various researchers in the field together. Thuy Tran, section head of the centre, talks about studies related to breast, pancreatic, thyroid, and prostate cancer.

Two such drugs are already on the market. The first, Lutathera, can be used to treat neuroendocrine tumours of the pancreas when the disease has spread in the body. The other drug is Pluvicto, which can be used for metastatic prostate cancer. In both cases, the treatment involves the substance lutetium-177.

However, their use in Swedish healthcare has been sparse. The drugs are very expensive and have so far only been given in advanced disease where the metastases have become resistant to chemotherapy. In this patient group, some have gained a few months of extended survival ‒ but others several years.

Thuy Tran and her colleagues are working to increase the treatment efficacy of these radioactive drugs. One way is to use substances that emit more powerful radiation ‒ that is, a higher radiation dose to individual cancer cells. Another approach could be to treat earlier.

"We believe there are significant benefits to be gained if these drugs can be administered before the disease has become so advanced," says Thuy Tran.

The high cost of the drugs is partly due to the fact that they must be manufactured on-site at the hospital, usually on the same day they are to be administered, because the radioactive substances have a short half-life. And all staff must be protected from the radiation source, from the chemist who manufactures the drug to the healthcare staff who administer it to the patient. The staff must wear dosimeters that measure the radiation dose.

"We have recently received a grant from Vinnova to work on improving access to these drugs throughout Sweden," says Thuy Tran.