It’s a remarkable paradox of cancer treatment that radiation, a well-known cause of cancer, is also a cornerstone treatment. Safe doses of radiation can also play a part in diagnosis. Scientists working within the NIHR Biomedical Research Centre (BRC) at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London have been working to improve diagnosis and treatment for cancer though the use of radiotracers – radioactive molecules that bind to cancer cells.  

Positron emission Tomography (PET) scans are routinely used in the process of diagnosing cancer. The patient is injected with a safe dose of the radiotracers, designed to collect around tumours. The patient is then scanned to see where radiation accumulates, which highlights the area of cancer cells. This creates detailed and accurate images of tumours that can be used to guide treatment, while leaving the healthy tissue unharmed.

Sugar or spice

The standard radiotracer for PET scans is Fluorodeoxyglucose (FDG) a substance similar to glucose. It tags cells in the body that are using a lot of glucose, such as tumour cells which grow quickly and therefore use more sugar than most cells.

Researchers at the King’s College London School of Biomedical Engineering and Imaging Sciences are looking at ways to tag the radioactivity specifically to the tumour cells, and not just any cell with a high sugar uptake.

As part of a project funded by the NIHR Guy’s and St Thomas’ BRC, Professor Phil Blower’s lab have been developing several new radiotracers, including one, designed to scan men with prostate cancer.

The radiotracer is based on Gallium-68, a positron emitting radionuclide. The team have developed a technique to quickly and easily bind Gallium-68 to a urea based small molecule. This molecule in turn binds strongly to Prostate-specific membrane antigen (PSMA) that is strongly expressed in all prostate tissue cells, and particularly cancer cells. This combination forms the compound Gallium-PSMA which binds specifically to prostate cancer cells and can help create detailed images.

A particular advantage of the method developed by Professor Blower to make Gallium-PSMA is that the urea based small molecule can be labelled in minutes in a single step using a freeze dried kit, unlike other types of PSMA which are more difficult to make. This may seem like a minor moderation to the methodology, but the positive impacts from removing a stage from the production process can make a big difference. Existing methods of producing radiotracers take longer, meaning much of the radiation is lost from the Gallium. This in turn means the scans are less effective, and that fewer scans can be completed with a batch of radiotracer.

The simplified method for producing the Gallium PSMA could improve on the current techniques, resulting in shorter waiting times, faster and more accurate diagnosis and reduced staff time producing the radioactive tracer.  

All hands on deck

Imaging with radioactivity involves scientists from different fields to bring this technology to the clinic. Professor Blower, as a chemist, works on the radioactive material itself. Biologists are then involved to ensure the radioactivity tags to the right cells, and check that it has no other effects on living tissue.

Then a host of radiopharmacists, technologists, radiographers and physicists and are required behind the scenes, to produce the tracers, take the scans and ensure that the image quality is of the highest possible standard.

The Gallium-PSMA technique has gone through clinical trials to test its safety and efficacy. People might more commonly think of clinical trials as being used to develop new treatments, but they’re needed for improving imaging techniques and diagnosis of disease too.

At Guy’s and St Thomas’, the technology is now being actively used as part of routine practice for diagnosing prostate cancer, as the Trust is in the unique position of having both the scanning and the radiopharmacy facilities to deliver it.

In the clinic

Professor Gary Cook, Professor of Clinical PET Imaging and Dr Victoria Warbey, Consultant in PET Imaging at the King’s College London and Guy’s and St Thomas’ PET Centre have been using the Gallium-PSMA radiotracer in the clinic for over a year and have scanned more than 250 patients.

Professor Cook highlighted how important it is to have the right infrastructure in place to apply this technique.

“Every morning Vickie Gibson, lead radiopharmacist, and her team produce the tracer in the Nuclear Medicine Radiopharmacy at Guy’s Hospital. It’s then transported to us over at St Thomas’, where we use it to scan patients. In addition, we’re lucky that we have two scanners, so we can have two patients being scanned at the same time. This maximises the efficiency of the tracer production.”

Patients who undergo PET scans with the Gallium-PSMA fall into two groups: those who have just been diagnosed with prostate cancer, and those whose prostate cancer was in remission, but their doctors think the cancer may have returned.

In patients who are newly diagnosed with cancer, doctors are choosing between a range of treatments, balancing the likelihood of success with the impact on the patient. It might be that in a smaller tumour, surgery or radical radiotherapy will be enough. If it has spread, chemotherapy may be needed to shrink the tumour before surgery. If it has spread very significantly, doctors might not be able to do surgery, and recommend hormone therapy or other treatments.

“It’s early days, but we think the Gallium PSMA is showing an improvement on the current PET methods, as it can detect much smaller volumes of cancer”, says Professor Cook.

“We think as many as a fifth of newly diagnosed patients who had a Gallium-PSMA scan may have been given a different treatment in light of the additional information the scans gave us. This might mean we found out they needed more treatment, or it may mean we found they didn’t need as much treatment, so patients didn’t have to go through unnecessary treatment and the associated side effects.

“In the case of patients whose cancer has returned, we think as many as a third may have had their treatment plan changed as a result of the information provided by Gallium-PSMA scans in addition to our standard MRI and bone scans. Time will tell, but it looks like this could make a huge difference to patients.”

The future of PET

Doctors are already using these methods to personalise treatment. Professor Sally Barrington has spent much of her career looking at how PET scans can help guide clinicians in how they treat cancer. Early in her career, she worked on two trials to see if taking a PET scan early on in treatment could improve outcomes for lymphoma patients, reducing side-effects and improving survival.

She found that conducting trials using PET imaging could be challenging. Based on her experience, she and colleagues founded the UK PET Core Lab based at St Thomas’ Hospital, an initiative to ensure there’s a standard for sites taking part in multicentre trials. The Core lab works to harmonise practice across the UK and ensure images are of sufficiently high quality to all be used in the trials to investigate new treatment approaches.

In 2017, she was awarded an NIHR Research Professorship to expand this work, and to help improve how PET scans are used by clinicians across the country.

An exciting new area is developing tracers that tag to oxygen-deprived cells. Some tumours grow very big and because they have a disrupted blood supply, the cells at their centres are starved of oxygen. Instead of simply dying away, these tumour cells seem to be able to survive and are likely to be resistant to radiotherapy.

“We’re working with Professor Blower’s lab to develop tracers that tag to these cells, which could help us identify tumours that are more likely to be resistant to radiotherapy.” says Professor Barrington. “Then we would know in advance where a patient might need a higher radiotherapy dose or that we need to use another treatment.”

Professor Barrington is also working to adapt existing methods to monitor patients’ treatment.

“We’re now looking at many different therapies that are available for cancer treatment, and we need to develop the way we read PET scans to adjust to this.

“Immunotherapies, for instance are a major development. These therapies boost the immune system and enable immune cells to attack the tumour. However, we don’t know much about how a PET scan should look in a patient who has just had this treatment. The tumour might get bigger before it gets smaller because of the immune cells. We need to understand how to read what’s happening in patients who have had these treatments.

“There are so many exciting developments, and as researchers we need to constantly adapt our methods so that we’re providing the most accurate information possible, and guiding doctors to make the best decisions for patients’ treatment.”