Reducing the dose and duration of radiotherapy treatments for anal cancer may result in fewer side effects, recent clinical trial results have shown.

The study, called PLATO, is run through the Leeds CRUK Clinical Trials Unit at the University of Leeds and is funded by Cancer Research UK and Stand Up To Cancer. It consists of three clinical trials (ACT 3,4,5) that are designed to optimise radiotherapy treatment for patients with anal cancer.

The ACT 4 trial is the first clinical trial in the world to randomise patients between standard and lower dose treatment in anal cancer. The short-term findings have been presented at the 2023 European Society for Therapeutic Radiology and Oncology (ESTRO) congress, the largest European radiotherapy conference.

The presentation was given by Dr Alexandra Gilbert, Associate Professor of Clinical Oncology at the University of Leeds. It detailed that while the ACT 4 groups were not statistically compared, the PLATO team observed that at six months a lower dose radiotherapy resulted in a high level of complete disappearance of the cancer with fewer side effects and improved sexual function than observed for patients receiving standard dose treatment.

Across both groups there was a high rate of complete response of the cancer at six months - meaning all signs of cancer had disappeared in response to treatment for both low and standard doses of radiotherapy.

The PLATO ACT 4 presentation detailed the short-term results up to six months. Further follow-up is required to determine the impact of lower dose radiotherapy on local recurrence of anal cancer and the results are expected next year.

Professor David Sebag-Montefiore is the Chief Investigator for PLATO and an academic clinical oncologist at the University of Leeds. He said: “The side-effects of radiotherapy treatments have a significant impact on the lives of patients and their friends and families, and we are very encouraged by the ACT4 trial results using lower dose radiotherapy.

“The current approach for anal cancer treatments is essentially a ‘one size fits all’ where the dose of radiotherapy is similar whether the tumour being treated is very small or very large. If we could offer tailored approaches without compromising cure rates, this could prevent patients from suffering side effects unnecessarily.

“The PLATO’s ACT4 trial results is an important step towards a personalised approach for anal cancer and using a smarter, kinder approach to treatment.”

Patient’s quality of life

Anal cancer is a rare disease with roughly 1,500 cases diagnosed in the UK every year but the incidence of the disease is set to rise by 14% over the next 15 years.

The current standard of care for anal cancer is chemo-radiotherapy. While this practice results in relatively high cure rates there are significant side effects as a result. Some of the most common side effects of radiotherapy include sore skin, diarrhoea, incontinence, fatigue, vaginal irritation and loss of sexual function.

Dr Gilbert said: “The global standard of care for anal cancer has not changed for more than two decades. The current approach is associated with significant short-term and long-term side effects and high-quality evidence is required to determine the best dose of radiotherapy for tumours of different sizes and the degree of local spread.

“Despite its rarity, we are able to successfully complete clinical trials to provide vital evidence that will help decide the best treatment for future patients with anal cancer and help preserve their quality of life.”

The ACT4 PLATO trial

The PLATO team collaborated with colleagues from across the UK in the development and implementation of a novel radiotherapy approach, intensity-modulated radiotherapy (IMRT).

IMRT reduces the sides effects of treatment and allows different radiotherapy doses to be applied to the visible cancer, which requires a higher dose, and a lower dose to the surrounding lymph node areas at risk of containing cancer cells at the same time.

It also provides the basis for testing the personalisation of radiotherapy dose delivered to the visible tumour.

The aim of the ACT4 trial was to determine whether a lower dose, shorter course of radiotherapy combined with chemotherapy can reduce the short-term and long-term side effects of treatment and still achieve the same high rate of local eradication of the cancer that is achieved using a standard dose of radiotherapy combined with chemotherapy.

The ACT 4 trial recruited 163 patients with anal cancer up to four centimeters in size that had not spread to the surrounding lymph nodes. They were recruited from 28 sites in the United Kingdom between Jan 2017 and Dec 2020.

The current standard treatment, determined by previous randomised trials, is a total dose of 50.4Gy given as 28 out-patient radiotherapy treatments over five and a half weeks combined with chemotherapy over the same time period.

The shorter course of treatment evaluated in ACT4 is 41.4Gy given as 23 out-patient radiotherapy treatments over four and a half weeks combined with chemotherapy over the same time period.

Sarah Brown, Professor of Cancer Clinical Trials Methodology said : “PLATO is a fantastic example of a ‘team science’ approach working in collaboration with experts in anal cancer, clinical trials, radiotherapy, cancer biology, data science and computation and imaging in Leeds and across the UK. The umbrella trial design with three trials in one means we can do this efficiently, taking steps towards more personalised therapy in the future”.  

The ACT4 trial co-leads are Professor Richard Adams (Cardiff University) and Dr Mark Harrison (Mount Vernon Hospital). There is a wider Clinical Trials Unit team and Trial Management Group that includes a patient and public involvement representative.

Executive Director of Research and Innovation at Cancer Research UK, Dr Iain Foulkes, said: “Anal cancer is a devastating disease, and treatment often comes with life-altering side-effects. There is a real need for treatments which can help people live a better quality of life.

“The PLATO trial has been an outstanding example of working smarter with existing resources, harnessing the latest advances in radiotherapy to target cancer cells and leave healthy cells intact.

“We are really pleased to see that smarter use of radiotherapy minimises these side effects. We look forward to seeing the longer-term results that we hope will result in changes in how we treat anal cancer in the clinic.”

Encouraging patients to join clinical trials – Rosie’s story

Rosie Sanderson was diagnosed with anal cancer in 2019 when she was 61 years old. She joined the PLATO trial as part of its randomised patient set.

Four years ago, Rosie started experiencing breathlessness and following tests with her GP she was initially diagnosed with anaemia as a result of anal bleeding. Rosie had attributed this symptom to a previously existing condition. This is not uncommon for people to ignore instances of anal bleeding, sometimes believing it to be caused by other conditions such as haemorrhoids, diarrhoea or constipation. But it is one of the few early symptoms of anal cancer. 

After a colonoscopy and biopsies, it was confirmed she had anal cancer and was referred to St. James under Professor David Sebag-Montefiore’s team.

Rosie was immediately interested in the possibility of joining a clinical trial, which she discussed with her attending doctor. Rosie said: “I’ve always been aware of the importance of clinical trials for improving treatment, especially for rare diseases like anal cancer.

“It was made clear to me from the start that being a part of a clinical trial would not compromise my care. I felt assured that my health remained the priority throughout the trial.”

As part of PLATO ACT4 Rosie received the standard dose of radiotherapy across five and half weeks. Because the trial was randomised Rosie did not know which treatment method she would receive when she signed up. Rosie also received a course of chemotherapy, as a standard part of treatment for anal cancer.

She said “Two to three weeks into my treatment I really started to feel the side effects, particularly pain and fatigue. By the fourth week, I was no longer able to travel by train or drive myself to treatments. Before I started the treatment, I was a really fit and active person. That loss of independence and the constant exhaustion were a real challenge for me.”  

Rosie was declared cancer free in 2020 with a planned follow-up for five years. While she still suffers some long-term side effects, the pain and fatigue faded in the weeks following the end of her treatment. Rosie is still part of PLATO and continues to answer regular questionnaires to track her long-term side effects and health.

Rosie says: “Having been through the treatment for anal cancer, I fully appreciate how helpful it would be to have more options in care. The possibility that future patients might not have to face as many side effects and have shorter treatment is really wonderful. 

Rosie says: “To anyone considering joining a clinical trial my advice would be: go for it!  Make sure your doctor knows you’re interested. They know what options are available and together you can decide if it’s right for you.

“Clinical trials allow researchers and doctors to find better ways to help people and it feels really good to be a part of that.”

Source: University of Leeds