How do you prevent unnecessary or ineffective treatments in patients with a difficult to treat disease?

Head and neck cancer is an often overlooked disease that can only be tackled through innovation in delivering complex clinical trials.

In the mid-1970s, the UK started to see a growing awareness of the harmful effects of smoking. TV adverts, billboards and even a villainous appearance in Superman comic strips pointed to a world that started to understand it as a significant risk factor for many diseases, including head and neck cancers. 

Despite that promising trend, head and neck cancers are on the rise. The reason? HPV. 

Human papilloma virus (HPV) is the name for a group of sexually transmitted viruses that affect the skin and the membranes lining the body. It is a risk factor for cervical cancer, and in the recent years has emerged as the most significant driving force behind the increase in head and neck cancers.

Professor Hisham Mehanna, Director of the Institute of Head and Neck Studies and Education (InHANSE) at the University of Birmingham, explains, “HPV related cancers are on the increase across the world. In the UK up to 70% of throat cancers are due to, or related to, HPV and a decade ago this wasn’t the case. Fundamentally it’s due to a change in sexual practice, and for head and neck cancers it is strongly associated with oral sex and large numbers of sexual partners. It’s something that probably started really in the sexual revolution of the late 1960s, but took decades to fully develop into the common risk factor that we see today.”

As with any change in epidemiology for a disease, the research community has had to realign their focus. Having done so, the research team at InHANSE are now at the forefront of global efforts to combat HPV associated head and neck cancers on multiple fronts.

Science moving forward, but the field remains overlooked

As with many areas of cancer research, there has been an urgent shift towards understanding the possible role of immunology in treatment, the use of robotics in surgery, and a desire to improve palliative care for patients.

In particular, the incorporation of immunotherapy and the fact that it appears to show positive results for head and neck cancer has boosted interest from pharmaceutical companies who have identified the opportunity. That interest brings hope of greater thrust behind clinical trials; on the face of it a dose of good news for an often overlooked area.

“Head and neck cancer tends to be something of a forgotten area,” says Professor Mehanna. “It’s not as prevalent as some of the more common cancers; lung cancer, colorectal cancer and breast cancer; and the outcomes are often more positive than many, including pancreatic cancer. So despite the big rise – in Scotland, for example, it’s the fasting rising cancer - the funding and public awareness is yet to follow. There’s a disconnect there that needs bridging.”

What this shortage of funding means, however, is that research clusters have had to think even more innovatively and focus on maximising the value of the resources they have.

That is not to say that the InHANSE team are short of impactful projects. They are a small team in terms of numbers, but prolific in terms of research. One glance at the acronym filled whiteboard in Professor Mehanna’s office highlights the vast range of trials and studies underway across translational and molecular medicine, clinical effectiveness, and quality of life and functional outcomes. The global influence of the small team is significant and growing. 

Getting to grips with an emerging cancer

With HPV associated cancers being relatively new on the scene, there comes an urgent need to understand the mechanisms by which the cancer operates. 

“It’s actually quite rare to be presented with an emerging disease, it brings a new challenge for sure,” explains Professor Mehanna, “we have to build the foundations of understanding and work from there.”

The InHANSE team have a particular interest in investigating biomarkers that can be used to predict the response of patients to certain treatments, or whether a person will go on to have a certain type of cancer in later life. These markers are usually either proteins or gene-based molecules within the cells with the aim of being developed to become tests that can be used in routine clinical practice.

The PREDICTOR study, headed by the Birmingham team, has proven to be a significant breakthrough in this area. A world-first, it outlines a marker that can determine which patients would benefit from surgery, and which patients would benefit from standard chemotherapy.

Such advances can both add to our understanding of the cancer itself, and help clinicians to monitor and treat patients in the best possible way.

Indeed, another facet of the InHANSE work is improving the clinical effectiveness of proposed treatment. The team are involved in a number of studies from various stages of clinical trials to systematic reviews, always looking at improving outcomes for patients, cost effectiveness and checking the viability of proposed treatment pathways in their early stages.

A good example of this can be found in the De-ESCALaTE trial – a much needed acronym for the full trial name: Determination of epidermal growth factor receptor-inhibitor (cetuximab) versus standard chemotherapy (cisplatin) early and late toxicity events in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

The findings of said trial were recently announced in Munich as a presidential address for ESMO 2018 (European Society for Medical Oncology), the second largest gathering of oncologists in the world – and answered a question that had long been debated in the field.

The question centred on the use of a targeted agent – cetuximab – and whether it could reduce the long term effects of toxicity in HPV positive patients. 

Professor Mehanna outlines why it was such a crucial question, “HPV positive patients tend to be a younger demographic than those who normally receive chemoradiotherapy, and their exposure to the toxicity that comes with it can mean really long term impacts on their quality of life. We looked at the role that cetuximab could play in treatment and found that not only did it fail to reduce toxicity but it actually did not cure as many people when compared to the traditional treatment. It is essential that we ask these questions and conduct these trials so we can improve the treatments that we, as clinicians, can offer our patients.”

With emerging fields, such as HPV related head and neck cancer, the role of researchers can often be as much about finding the right questions as it is about finding the answers.

The InHANSE group have become experts at putting together smaller studies that do exactly that, pinpointing the questions that would merit a costlier large trial that could take years to complete.  

Systematically reviewing fragmented information

The Birmingham based team have also completed a number of evidence syntheses using the information already available. Professor Mehanna says, “Research around cancer, particularly head and neck cancer, can be quite fragmented. There are a lot of questions that we’d like to investigate that don’t have a clinical trial to support the evidence base, but have a number of smaller pieces of evidence scattered across other areas. That can be problematic. If the surgeons read surgical journals, and the medical oncologists read the medical oncology publications, you’re not going to get a holistic, unbiased view about the best way forward. That’s where you need people like us to complete a systematic review across all of the literature.”

The PET-NECK trial, which published key findings in 2016 is a case in point. 

“To be honest, I wanted to prove to the oncologists that they were wrong in their approach,” admits Professor Mehanna. “There was a debate about whether or not we should undertake neck dissection before or after chemoradiotherapy with advanced-stage patients. We believed that it should be before, they said it should be after.”

“In fact, the systematic review of the literature told us that we probably shouldn’t be doing neck dissection at all if the tumour could be assessed with a PET-CT scan. That’s something that you can only get with a holistic viewpoint, and led us to doing the larger PET NECK study which answered the question definitively.”

The team certainly use a range of approaches. From original research, to trials, to reviewing the pre-existing literature. But sometimes solutions can be along even less common paths, by repurposing solutions from other parts of medicine entirely. 

Redeployment as a possible pathway for success 

The AcceleraTED programme run by the InHANSE team looks beyond the traditional approaches for drug development and instead looks at drug redeployment. The team screen already licensed drugs that were designed for other diseases for efficacy against cancerous cells, with the aim of finding candidates that could be repurposed for the cancer field.

“This is a significant piece of work that has already shown some very interesting findings,” says Professor Mehanna. “There are a lot of drugs approved for use in humans, but only a small number developed for use in tackling cancer. The rest have never been tested for efficacy against cancer.”

The team have already screened over a thousand drugs on high throughput platforms and identified a around twenty that have shown some effectiveness against head and neck cancer cells grown in the lab. One drug of the seven that have currently completed their full testing is showing very good signs and likely heading towards a clinical trial.

A further advantage of redeployment comes in toxicity profiling. Because the drugs have already been tested, the toxicity is a known quantity. With 25 per cent of new drugs failing testing due to their toxicity to human cells – it represents a potentially huge cost saving.

Despite that promise, Professor Mehanna outlines the difficulty facing drug repurposing efforts, “This is a very intensive process to get to this point, and sadly it’s not fashionable for funders. We’re eternally grateful to the QEHB charity and Get Ahead charity for supporting our drug repurposing work to this point. It’s a great shame that there isn’t more work done in it, but we are hopeful that these early findings will encourage more support.”

“There has been a big push over the last decade towards targeted treatments. There’s a pathway, there’s a mutation, and you need a drug to target that mutation. The problem with that is that cancers are an adaptable system, and the idea of a single mutation being able to stop a cancer for good works only for a very small number of cancers. In many, when you target one mutation, it might stop for a while, but the cancer will find another pathway. Think about cetuximab. That’s an EGRF inhibitor - a targeted drug – and we’ve shown to not be effective in our De-ESCALaTE trial.” 

A viable treatment for everyone

Talking to Professor Mehanna, it seems that drug repurposing is an obvious area for greater focus, not least in tackling head and neck cancers in lower or middle income countries.

Immunotherapy costs between £30,000 and £90,000 per patient for the full course of treatment, and as such is not accessible to a significant portion of the world’s population. But a repurposed off-patent drug that shows some efficacy could cost pennies and have live-changing implications for a number of patients. 

“We need to recalibrate some of our thinking about drug development and who we are developing these drugs for,” states Professor Mehanna. “We need to take a step back and think about our aim. On a global scale, personalised medicine isn’t just about choosing the ideal treatment for the right person at the right time, but also about choosing the right treatment that is viable within that setting.”

“Repurposed drugs might not be quite as effective as more expensive targeted options but it could help to move that dial in the right direction. And the two treatments aren’t at all mutually exclusive, they help each other and become synergistic. If you do find a repurposed drug, you can break it down and find out the mechanisms that it uses. That can become the basis of targeted treatments.”

The idea that redeployment could provide insight for the translational and molecular scientists takes us full circle. It speaks to the importance of a team who cover head and neck cancer from every angle – providing a truly holistic approach to improving patients’ lives through research. 

Against a backdrop of rising prevalence and in a field often overlooked for funding, it would be easy to be pessimistic about the direction of travel. But with the UK approving a HPV vaccination for boys (it is already available to girls), and the combined efforts of charitable funders and the international research community, Professor Mehanna is cautiously optimistic.

“A new vaccination might take 30 years to have an impact, but it’s a positive step. What we are seeing is more advocacy that comes with a younger demographic of head and neck cancer patients. So there are positives. And so long as that advocacy continues and research groups like ours can continue to make breakthroughs, I remain really positive about the future of the field."

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