World Radiography Day 2023: Centre For Trials Research Radiotherapy Trials And Beyond

Authors: Sarah Bridges, Christie Heiberg, Lisette Nixon, Jack Pritchard, Ann White

BACKGROUND

World Radiography Day marks the anniversary of the discovery of x-rays by Wilhelm Roentgen in 1895. Soon after Roentgen’s discovery, scientists began experimenting with x-rays on living tissue, learning that they were an effective method of stopping cancer cells from multiplying.  Research continued into the treatment of various types of cancer, and, since the 1930s, radiotherapy has been a mainstay of cancer treatment.  To celebrate this day, we are highlighting the expertise of the Centre for Trials Research in running radiotherapy trials that refine our knowledge of radiotherapy treatments.

Radiotherapy has become a crucial part of the treatment plans for as many as half of all cancer patients and is responsible for around 40% of successful treatments⁽¹⁾. Over the years, radiotherapy research has led to significant advances:

• Radiotherapy has evolved from a single, large dose of radiation to a more effective approach of delivering radiation in smaller, daily doses. Radiotherapy dose is measured in Gray (Gy) and split into a number of fractions. The dose for each fraction is added up to give the total treatment dose. For example, a typical dose of 50Gy may be given in 25 fractions of 2Gy each.
• Conformal Radiation Therapy (CRT) has been introduced, using 3D CT images to precisely map the shape and location of the cancer, making treatment much more targeted and accurate. Specialist software has been developed that calculates how much dose each point of the tumour and surrounding cells receive. Some hospitals now use 4D planning too, which accounts for the movement involved when breathing. In the past, if a patient was scanned while taking a deep breath the position of a tumour in the chest or abdomen could differ significantly when they exhaled, making it difficult to ensure precise radiation delivery. 4D planning takes this natural movement into account, ensuring that the right radiation dose is directed at the tumour regardless of whether the patient is inhaling or exhaling.
• Intensity Modulated Radiation Therapy (IMRT) is now commonplace in radiotherapy centres throughout the UK. This allows the radiation dose to be shaped to precisely match the shape of the tumour as well as target it from different sides, meaning normal tissue and organs close to the tumour will be at less risk of receiving high doses of potentially harmful radiation.
• Proton beam therapy is another exciting development using protons instead of traditional x-rays. This technology allows the radiation to pass through normal tissues with minimal damage, making it a more precise and less harmful option to healthy cells around the tumour.

The effectiveness of radiotherapy has improved significantly through these developments, reducing the impact on healthy tissue and offering new hope to many cancer patients. However, only 2.8% of cancer research funding goes into radiotherapy-specific research ⁽²⁾ and radiotherapy research makes up just 9% of all cancer clinical trials worldwide ⁽³⁾.  Despite this, radiotherapy research continues to make progress, and the radiotherapy portfolio that CTR runs in collaboration with its Sponsors and partner organisations ensures that existing knowledge continues to be built upon in order to improve outcomes for patients.

RADIOTHERAPY TRIALS MANAGED BY CTR

SCOPE2

SCOPE2 is a research study sponsored by Velindre University NHS Trust, which investigates whether a higher dose of radiation (60Gy instead of the usual 50Gy, given alongside chemotherapy) can improve how we treat oesophageal cancer.

Purpose:  The advent of technologies such as IMRT allows us to shape radiation to align with the shape of the tumour. We want to find out whether a higher dose of radiation can improve outcomes for patients without causing additional harm to the healthy tissue surrounding the tumour.

Progress: SCOPE2 started recruiting patients in 2016 and includes 38 hospitals across the UK. The aim is to recruit a total of 430 participants into the study by the end of December 2023 and there have already been over 400 participants recruited. Participants will be followed up for a minimum of 2 years.

In a Nutshell: SCOPE2 aims to improve outcomes for patients with oesophageal cancer. The trial  could change how we treat this type of cancer in the future and improve outcomes for patients.

 “The UK Collaboration that has supported the SCOPE 2 trial is one of the best things that I have been involved with in my career. SCOPE 2 is, as far as we know, the largest definitive oesophageal chemoradiotherapy trial to have been delivered. It is probably also the last chance globally to answer the question about the value of dose escalation. Whatever the results show, I am convinced that this study has improved the quality and consistency of Upper GI radiotherapy throughout the UK”
– Prof Tom Crosby, Chief Investigator of SCOPE2

PEARL

PEARL is a feasibility study, sponsored by Velindre University NHS Trust, investigating the benefits of adaptive radiotherapy in HPV driven oropharyngeal cancer in an attempt to reduce side effects and improve quality of life in patients undergoing curative treatment. PEARL is funded from the Velindre Advancing Radiotherapy Fund (formerly Moondance).

Purpose:  A course of chemoradiotherapy to an oropharyngeal cancer can be exceptionally toxic and challenging for patients. Typically patients have their radiotherapy planned at baseline; however it is well established that tumours shrink during a course of treatment. PEARL is looking to adapt a radiotherapy plan halfway through treatment utilising a PET CET through collaboration with PETIC (Positron Emission Tomography Imaging Centre) at Cardiff University. This allows us to target shrinking tumours and minimise the dose to normal healthy tissue nearby. With less dose to normal tissue we believe there will be an improvement in side effects and subsequent quality of life. PEARL will investigate the predictive capabilities of PET CT scans and circulating tumour DNA (ctDNA) by correlating changes with clinical outcomes. Through further collaboration with Cardiff University, PEARL is investigating the role of an automated contouring algorithm, “ATLAAS”, in defining the primary tumour for targeting.

Progress:  PEARL opened in 2020 and is recruiting patients in 5 hospitals in the UK. We have already recruited 37 participants, and plan to finish recruitment by January 2024.

Participants will be followed up for a minimum of 2 years.

In a Nutshell: The aim of PEARL is to see if using technology can improve outcomes for patients with head and neck cancer. The results of the study will potentially be used as a basis for larger studies in the future, designed to prove that PET-based radiotherapy plan adaptation can reduce side effects for patients.

PATHOS

PATHOS, co-sponsored by Cardiff University and Velindre University NHS Trust, aims to tailor treatments for patients with HPV-positive oropharyngeal cancer in order to reduce side-effects and improve the quality of life.

Purpose is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in treatable disease will improve swallowing function and disease-free survival.

Participants undergo surgery and are placed into an appropriate treatment group according to their risk (determined by the pathology report):

Group A – low risk – no further treatment

Group B – intermediate risk – radiotherapy alone and randomised to standard dose (60Gy over 6 weeks) or a lower dose of post-operative radiotherapy (50Gy over 5 weeks)

Group C – high risk – radiotherapy with chemotherapy or radiotherapy alone at the standard dose (60Gy over 6 weeks).

Progress:  1030 participants have been recruited internationally, making this the largest head and neck cancer study in the world.  There are 40 sites in the United Kingdom and 17 sites across France, Germany, Australia and the United States. Participants will be followed up for a minimum of 5 years.

In a nutshell: By potentially reducing the intensity of treatment, such as through lower-dose radiotherapy or omission of chemotherapy, researchers hope to minimize long-term side effects while maintaining cure rates.

“I am privileged to be one of the Research Partners on PATHOS, providing a public and patient perspective to the research team.  The study has patient wellbeing at its heart, and is being conducted with such care and respect for each individual participant, despite the scale of the project.  The ongoing inclusion of the public/patient voice is testament to the patient focussed ethos of the research team and the project as a whole, with input and opinion sought on all aspects of the work, and suggestions acted on appropriately.  For example, I was particularly pleased with the introduction of a participant focussed newsletter, keeping patients up to date on progress and thanking them for their important contribution.”
– Sarah Peddle, PATHOS Research Partner

SCC-AFTER

SCC-AFTER is a research study sponsored by Cardiff University for people with cutaneous squamous cell carcinoma (cSCC), a common non-melanoma skin cancer. It is the first trial of this kind  in the world.

Purpose: To investigate whether in patients with high risk but completely excised cSCC, giving radiotherapy in addition to close clinical follow up (versus close clinical follow up alone) is beneficial in reducing loco-regional recurrence. Excised cSCC is where the tumour has been removed surgically and the outer edge has been checked by pathology for no cancerous cells. The cancer may return in this area (loco-regional recurrence) and risk factors have been identified that increase the likelihood of this. Radiotherapy may help reduced this recurrence, but this needs to be shown in a randomised trial.

We will monitor all patients for cancer recurrence, treatment side effects and quality of life.  The study is actively looking to include patients who are traditionally under-represented in trial participation, for example, older/frailer patients, those with multiple long-term conditions (e.g. heart or lung disease), those who are immunocompromised, and patients from socio-economically disadvantaged groups. If the study shows radiotherapy is effective in preventing recurrence of cSCC, we will be able to recommend its use as a routine NHS treatment.

Progress:  The trial will be starting soon and aims to recruit 840 participants at 25 NHS sites over 4 years. Participants will be followed up for a minimum of 3 years.

In a nutshell: The outcomes from this study will provide robust and reliable evidence to guide future national treatment recommendations and potentially improve patient outcomes.

“I have been a skin cancer patient in the areas of keratinocyte skin cancer over several years and embrace studies where there is the probability of improving the patients’ outcomes.  Cutaneous squamous cell carcinoma along with radiotherapy  is one such study”
– Patricia Fairbrother, SCC-After Research Partner

INVOLVING THE PUBLIC AND PATIENTS

CTR prides itself on our Patient and Public Involvement team who seek to include PPI Research Partners in all aspects of trial development and delivery.  They have input into all patient facing documents and are part of trial oversight teams such as the Trial Management Group, giving insightful input into trial implementation.

PARTNERSHIPS

Radiotherapy quality assurance

To ensure that we don’t have inaccurate or skewed results in our trials we need a system to mitigate the impact of different hospitals using a range of radiotherapy equipment and methods.  Our trials therefore incorporate Radiotherapy Quality Assurance (RTTQA) programmes (in collaboration with the National Radiotherapy Trials Quality Assurance Group) to ensure these differences are minimised and radiotherapy plans are completed to a high standard. Each of the hospitals running our radiotherapy trials needs to complete planning exercises and submit information about their facilities and processes, all of which need to be approved by the RTTQA team before the hospital can open to recruitment. The RTTQA team also reviews scans and plans of patients on-trial to check that the correct doses of radiotherapy are being administered to the tumour with minimal encroachment upon surrounding healthy tissue. If any adjustments are required we can let the sites know in real time, ensuring that the radiotherapy administered as part of the trial is of the highest quality it can be and standardised as much as possible across all of our hospital sites.

Site Research Radiographers

We work in close collaboration with Radiographers at hospitals across the UK. Here, Jack Pritchard from Velindre Cancer Centre explains the role of the Research Radiography team:

The Radiotherapy Research team at Velindre Cancer Centre are a small group of staff that are responsible for the set-up, running and implementation of Radiotherapy Trials within the department. The team consists of four research radiographers, one research officer and a trials administrator. The team deals with trials across all tumour sites and specialities where the main focus of the research question involves Radiotherapy. These studies may look at new doses for current treatments or even new treatment options that would have been previously unavailable to certain patients. The team will be tasked with setting up these new processes ready for the study to begin, then collect all of the relevant data and report this back to the trial centre for analysis. Over the years this has led to involvement in a variety of important national and international clinical trials that have led to the improvement of cancer care for patients both locally and further afield.

RESEARCH IMPACT

We have seen huge advances in radiotherapy treatment over the last century but know that ongoing research is required to continue to improve outcomes and quality of life for patients. CTR, through its portfolio of radiotherapy trials, endeavours to further knowledge in this field. We are very grateful to the organisations that fund this research, including Cancer Research UK (SCOPE2 and PATHOS), Cancer Research Wales and Velindre Advancing Radiotherapy Fund (formerly Moondance) (PEARL), and the National Institute for Health and Care Research (SCC After), and above all we are grateful to all those who have participated in our radiotherapy trials over the years.

“Radiotherapy is one of  the most important tools we have in treating cancer; for cure, for improving survival and improving quality of life. Technological advances and well designed NHS and academically led clinical trials in the UK continue to demonstrate the true value of this treatment modality, which has a lot more to offer in the future”

– Prof Richard Adams, Director of Cancer Trials, Centre for Trials Research

If you have any questions please feel free to contact ctr@cardiff.ac.uk.

Authors: Sarah Bridges, Christie Heiberg, Lisette Nixon, Jack Pritchard, Ann White

References

• Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193-9. doi: 10.7150/ijms.3635. Epub 2012 Feb 27. PMID: 22408567; PMCID: PMC3298009
• https://doi.org/10.1016/S1470-2045(23)00182-1
• https://doi.org/10.1016/j.ijrobp.2022.01.053