Q&A: Prof Ashkan & Mr Bhangoo

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Consultant neurosurgeons at The London Clinic on a highly promising clinical trial for a new brain cancer treatment

Interview: Viel Richardson
Portrait: Christopher L Proctor

What is the nature of the clinical trial you’re currently running?
Mr Ranjeev Bhangoo: We are part of the ‘INTRAGO 2’ phase three clinical trial. It is a multi-centre trial designed to examine the effectiveness of using intraoperative radiation therapy (IORT) on patients who are suspected of having a glioblastoma multiforme tumour in the brain. Glioblastoma multiforme is an aggressive type of tumour of the brain or spinal cord and is the commonest form of primary brain cancer.

Who qualifies for the clinical trial?
RB: The selection criteria are strict. Patients cannot have already undergone significant surgery on the tumour. They may have had a biopsy or limited surgery but there must be a clinically-indicated need for further surgery. They also cannot have had any other treatment such as radiotherapy or chemotherapy. This is crucial.

What happens to potential patients?
Prof Keyoumars Ashkan: Each prospective patient goes through a very strict protocol. We see them to ensure they pass the entry criteria. Dr Matt Williams, a consultant oncologist working on the trial with us, makes sure they have all the oncological tests and assessments they should have at this stage of their disease. This stage is very important because we need as much data as possible about the patient before they start treatment. If they meet all the criteria they will be admitted onto the trial.

How does IORT work?
KA: IORT is a form of radiotherapy—a highly targeted dose of high intensity radiation. Once the tumour has been removed, the x-ray source applicator is placed close to the wound, and this delivers the radiotherapy dose. The aim is to kill cancer cells that will still be there, but which cannot be seen. Because we are only affecting tissue around the tumour site, we can deliver much higher doses than if we were delivering the radio waves from outside the body in the normal manner.

What has the prognosis for these patients traditionally been?
RB: When Prof Keyoumars and I started in neurosurgery in the 1990s, the survival rate for brain tumours had not improved since the 1950s. Life expectancy was nine to 12 months post-diagnosis. Things have improved but there is still a clear need for new treatments to be developed. The problem is that brain cancers are uncommon, accounting for only one to two per cent of all cancers, so funding has never been a high priority.

Is the prognosis poor because of a lack of research or because of the nature of the tumour?
KA: I think both. Unlike other body parts where the number of different types of tumour is quite limited—around four to six—in the brain there are over 100 different types of brain tumour, and this doesn’t include cancers that have spread from elsewhere. Glioblastoma multiforme is only one of these types, though the technique may well be usable in other types of tumour.

Does that complicate diagnosis?
KA: Very much so. Even within individual categories it has been found that tumours are different when you do a full genomic analysis. In fact, if you sample different parts of the same tumour they can be genetically different, and if you sample the same tumour at different times results can change. This is what makes it so very difficult to treat. These are very unstable tumours that can change rapidly and adapt to the different treatments like chemotherapy. It makes them very difficult to characterise.

How does the tumour present?
RB: it can present in several different ways. The symptoms vary depending on where in the brain the tumour is. If it is in the frontal part of the brain it can present with altered moods and behaviour; in other areas it can affect speech, affect movement, causing clumsiness, impact on sight, cause seizures or cause several other symptoms. While headaches are possible, I want to reassure people that the chances of your headache being caused by a brain tumour are vanishingly small!

Unfortunately, these tumours can destroy an individual. They affect the personality and the way people interact. Often by the end the patient no longer recognises their loved ones, which is tragic. It means that for those of us who treat brain cancer, the work is very personal. We are unlikely to cure this in our lifetime, but we can hopefully manage it in such a way that people can retain their quality of life.

Is early diagnosis important?
RB: It’s always best to find cancer early, but that does not always make things straightforward. If the tumour is in an area of the brain that we call ‘very eloquent’—meaning an area that controls speech or movement—the diagnosis will likely be made relatively early, but treatment is much more difficult because we are working around parts of the brain that have a very obvious impact, leaving very little room for error. In other parts of the brain that control less obvious activities, tumours may be discovered much later and therefore be larger, but the location makes it much more amenable to surgery, so it is easier to deal with.

It seems surgery plays a key role with glioblastoma multiforme.
KA: Nowadays, we practice a very personal type of medicine. We characterise your brain tumour at a molecular level. That requires lots of tissue to ensure we have all the information we need across the geography of the tumour. This makes brain tumours an area of medicine in which surgery is becoming increasingly important, unlike other areas of medicine where new treatment advances are making it less so. But with brain tumours, for the foreseeable future surgery is the safest, quickest and most effective way of treating the patient. Oncologists we work with will always ask us if we can operate before considering other treatment options.

Is yours a randomised control clinical trial?
RB: Yes, it is. The great thing about the way the trial has been designed is that even as surgeons, we do not know whether the patient we are operating on will get the IORT or not until the last possible moment. This removes the chance of our decision making during the operation being influenced by us knowing which treatment path the patient is on.

How does that work?
RB: The IORT equipment is set up and ready to go. The procedure proceeds completely as normal until the tumour has been removed. Only then are we told if they are receiving IORT. If they are, the device is moved into place inside the tumour cavity and we deliver the radiotherapy dose. If they are not, the operation is over and we close up. This is an area where the advance in technology is key—in the old days this would not have been possible because the size of the equipment meant you had to take the patient to a dedicated radiotherapy suite for the IORT.

What is the trial designed to reveal?
KA: What we are testing is the efficacy of the IORT procedure. This makes it critical that there are no other differences along the treatment path of patients in the trial. After the operation, both groups go on to the standard treatment. There are strict post-operative protocols designed to ensure the trial criteria are adhered to, and we collect all the data we can from every patient. We also monitor them very closely as things go forward. It is also important to stress that in clinical terms the post-operative regime our patients go through is the same as people outside the trial would get, so the only clinical difference is the IORT treatment.

What happens to those that don’t get the IORT?
KA: A very interesting and consistent fact with all studies of brain tumour surgery is that all patients, whether they are in the control set or the treatment set, do better than patients who are not in the study.

Why is that?
RB: Attention to detail. You are being operated on by a surgeon who has a deep interest in brain tumours, so they are very engaged and have a high level of skill. Then there is the rigour of the trial around you. Everybody is on top of their game, because nobody wants to compromise a patient’s results through a mistake. Everything is being scrutinised far more than normal because the validity of the trial results depends on all the protocols being followed to the letter. Also, there are two sets of clinicians paying attention to you: the clinical team and the research team. Two sets of eyes pore over every detail so very little gets missed.

Will this potentially help all glioblastoma multiforme tumours?
KA: Unfortunately not. Some tumours will be inoperable because of their location, such as a very large tumour close to the brainstem. We could not operate on that without posing an unacceptable level of risk to the patient. We have to accept that this trial is not for everyone and there are still limits to what we can do.

What will you consider to be a success?
RB: For the purpose of this trial, we are looking to see if there is an increase in progression-free survival in patients after the procedure. That means an increase in post-procedure survival time without evidence of the tumour coming back. That is called the ‘primary end point’ of the trial. We also recognise that factors like quality of life are very important, so we also have what are called ‘secondary end points’. For these, we look at metrics that examine the impact of the procedure on the patient’s quality of life, alongside short and long-term side effects. This trial can offer real hope to people. We are monitoring patients in other clinical trials who are now several years past their procedure and doing well. When we first entered this area, we were told it was a waste of time because there was nothing you could do. Both Prof Ashkan and I get huge satisfaction at still being here over 20 years later making a real difference to patients and proving the doubters wrong.

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