The HOPON clinical trial: the doctor’s perspective

One of our highlights from 2014 was the huge success of Stand Up To Cancer.

More than 10 million people tuned in to watch it live on the night and helped us raise over £15.5 million to support pioneering new clinical trials. To mark its success, we’re going to look back at one of the clinical trials we were able to fund thanks to the money raised during the show’s first outing in 2012.

In a three-part series, we hear from three different people involved in the Hyperbaric Oxygen for the Prevention of Osteoradionecrosis (HOPON) clinical trial – the doctor leading the study, the research nurses, and a patient taking part.

In this first instalment, Professor Richard Shaw – the researcher leading the trial – shares the aims of the trial and why it’s important for patients.

The side effects of radiotherapy

The story starts with some good news – we’ve become good at curing people who have head and neck cancer. Although new treatments are coming along all the time, most people are treated with a combination of surgery and radiotherapy.

Most people with head and neck cancer are treated with a combination of chemo and radiotherapy

But this success can come with a price. If you are a long term survivor of head and neck cancer and had radiotherapy during the course of your treatment, there’s a risk of experiencing long term side effects.

The most serious side effect is something called osteoradionecrosis, or ORN for short. This is a condition affecting jaw bones that radiotherapy beams have shone through. The bones can be damaged by the radiotherapy and don’t heal as well as other tissues, because they have a limited blood supply. And the worst case scenario for this particular condition is where the bone dies completely.

It affects patients who have been successfully treated for head and neck cancer and can occur anytime after radiotherapy – even 20 years later in some cases. While it can arise spontaneously, it usually develops following dental work, particularly tooth extractions or inserting implants. Loss of bone can lead to patients suffering jaw fractures, experiencing a lot of pain, or having holes appearing in their faces where the jaw bone has collapsed.

Because more people are developing, and surviving, head and neck cancer, we’re seeing an increasing number of people with these long term side effects. We think around one in 10 patients who received radiotherapy to the head and neck develops ORN, but we need research to find out exactly how many patients are affected. And for many of these patients, treating it is worse than the original cancer treatment. So, as doctors, it’s something we’re desperately keen to avoid for our patients.

The conception of HOPON

Professor Richard Shaw (left) and one of the trial team in a hyperbaric chamber

The idea behind the HOPON trial began in the US during 1970s and involved the use of something called hyperbaric oxygen treatment. People are put in a chamber for a period of time each day, where the oxygen is at higher pressure than in air we normally breathe. It had previously been used in diving accidents, carbon monoxide poisoning and for people with wound healing problems.

The theory was that the increased oxygen re-invigorates damaged tissues and helps them heal quicker. And therefore might help repair jaw bones damaged by radiotherapy, preventing severe side effects from developing after dental surgery in cancer survivors.

A clinical trial was carried out in the early 1980s in Florida. Patients who had been given radiotherapy and later needed dental work were split into two groups – one was given hyperbaric oxygen prior to dental work, the other group wasn’t. The results showed that having hyperbaric oxygen treatment significantly reduced the risk of the patient developing ORN. But that original study was only one small trial, and with improvements in radiotherapy techniques, some doubts were creeping in.

We knew that the time had come to prove one way or the other if hyperbaric oxygen treatment works in preventing ORN in patients. And that’s the principle behind the HOPON trial.

Getting started

It all sounded simple and straight forward. First, design a modern clinical trial to find a more accurate figure for the proportion of head and neck survivors who develop ORN. Then test whether giving them hyperbaric oxygen prior to dental surgery reduced their risk of developing the condition.

The starting point was to work out how big the clinical trial needed to be and this involved input from the team’s statisticians. Together, we worked out that we needed around 200 patients in the trial to get a clear answer as to whether the treatment has the kind of impact we’re looking for.

Setting up a clinical trial is not a minor undertaking, and the expertise and support of the Liverpool Clinical Trials Unit was invaluable. We had to make sure the trial set out to ask a question that would ultimately improve the care of cancer patients, was thoroughly planned to provide this answer, and ethical to carry out. We also had to secure funding for the trial which, thanks to Stand Up to Cancer, we achieved. We were ready to go, but hit a few unexpected teething troubles.

A bumpy ride

Watch this animation about how a randomised trial works on YouTube

Randomising patients to receive either the hyperbaric oxygen treatment or nothing at all as a comparison is the biggest challenge I’ve faced, and the hardest to explain.

Normally a trial will compare two similar treatment plans. For example, you might say to a patient, we have a white pill and a blue pill. The white pill is the treatment you would receive normally for your type of cancer; the blue pill is one we want to test and it might, or might not be, better. Both options look equally attractive to the patients.

But for the HOPON trial, one treatment involves up to four weeks of daily visits to the hyperbaric oxygen chamber prior to surgery and a further two weeks afterwards, while the other option is no treatment apart from the surgery. Now we have a situation where trying the experimental treatment – something we’re not sure works or not – has a much bigger impact on the patients’ lives and suddenly looks a lot less attractive to them.

On the flip side, there are patients who would like to join the trial but only if they get the hyperbaric oxygen treatment, because they want any therapy that might reduce their risk of developing these side effects. But I can’t guarantee them the treatment and don’t know who will get what – that’s the whole point of randomly assigning patients to the different groups.

The daily visits to the hyperbaric oxygen chamber can throw another spanner in the works. Say we have two feet of snow, these daily trips may become impossible; whereas the patients receiving no treatment aren’t affected by these kinds of scenarios. Because the treatment is much more involved and complex, more people drop out and this skews our calculations. We’ve had to increase the size of the trial to compensate for this.

The other hurdle we’ve faced is a ‘Catch 22’ situation regarding access to the oxygen chambers themselves. NHS centres that had been funding hyperbaric oxygen treatment for decades heard about the trial. Upon realising that the evidence for the treatment wasn’t strong enough, some hospitals stopped funding it, so our patients no longer had access to a chamber. Thankfully, in some regions they still allowed access but only if the patient was enrolled in a clinical trial, so it worked slightly in our favour.

In terms of the politics, logistics, finances, and the difficulties of randomisation, it’s been a steep learning curve for me. Personally, this is the hardest thing I’ve ever tried to do, and I perform complex surgery.

The principle of uncertainty

One thing I’ve found to be really important in explaining the need for the HOPON trial is the starting point of uncertainty. If I can communicate that, I’m half way to success.

As surgeons we are trained to be confident and certain, and patients often look to us for definite answers. So it’s a big challenge for many of us to explain to patients that the best people in the world don’t know if hyperbaric oxygen treatment works or not and that’s why we’re doing this clinical trial.

It’s even harder at times to persuade other surgeons that we don’t have the answer. Many surgeons have a deep-seated personal opinion on whether hyperbaric oxygen treatment works or not, and persuading them that their opinion may or may not be right is often a more difficult task than explaining it to patients.

Bringing research into routine cancer care

Combining research, clinical trials and care is really important

As a doctor, I see lots of advantages to working in a cancer unit that’s running clinical trials. The trials bring more benefits than just offering new (and sometimes more effective) treatments to patients. There’s some evidence to suggest that it improves the overall level of care we can offer, whether a patient is part of a clinical trial or not.

One thing I really rely on is the excellent support from the clinical trials team. Once I have approached a patient and introduced the HOPON trial, I hand them over to the research nurses who provide more detail and answer any questions the patient may have. The research nurses are highly trained and very experienced at supporting the patients and giving them all the information they need. It’s great that patients have other members of the team as another point of contact as well as me.

What I find most satisfying about the research is that it’s different every day – I’m always doing something new, be it lab research, a clinical trial or a new technique in surgery. To be able use my skills to try and tackle cancer is a privilege. Research has also brought me access to global expertise, which has no doubt made me better at treating patients.

Where are we now?

About six in every 10 patients we approach about the HOPON trial agree to enrol, and we’ve now got about 130 patients out of our target of 220 participants. We’ve opened the trial in Aberdeen, Leeds, Bradford, Bristol, Portsmouth, Chichester, Birmingham, South Wales, Taunton, and now in Denmark.

So, despite early trials and tribulations, HOPON is now recruiting patients well and we are on target to reach our goals. It’s thanks to the generosity of the public donating and fundraising during Stand Up To Cancer in 2012 that we are able to run this trial – we couldn’t be more grateful for the support.

Professor Richard Shaw

Look out for the next post in this series from three research nurses who work on the trial, which will be published tomorrow.