The ‘INTRAGO 2’ phase three clinical trial is taking place in multiple global locations including London with the aim of testing the novel new technology called intra-operative radiotherapy (IORT) for brain cancer.
This offers surgeons the ability to deliver a high and localised dose of radiotherapy to a brain tumour bed during a patient’s surgery. We believe that an IORT boost in addition to standard treatment can improve survival. The approach has been demonstrated to be effective with breast and colorectal cancers and we are optimistic that this new technique can help many people with this aggressive form of brain cancer called glioblastoma multiforme (GBM).
Treating brain cancer
GBM is the most deadly and common type of primary malignant brain tumour. Life expectancy was nine to 12 months post-diagnosis when we started our careers in the 1990s. This prognosis has improved but there is still a clear need for new treatments. The problem is that brain cancers are uncommon, accounting for only one to two per cent of all cancers, so funding hasn’t been a high priority.
One of the reasons why GBM tumours are so difficult to treat is that they are rapidly growing. Within one to three months, the number of cells in a GBM tumour could have already doubled. In standard care for GBM outside of this clinical trial, the patient will undergo surgery and then must wait a period of time before starting additional (or adjuvant) therapy such as external beam radiotherapy and chemotherapy.
The delay is because the patient needs time to heal but also time is required to prepare the radiotherapy treatment. During this delay, any microscopic remnant disease left behind after surgery will have already started to re-populate. The advantage of IORT is that it may be able to bridge the gap between surgery and standard additional treatment.
IORT works by delivering X-rays through a miniaturised device into the tumour cavity while the patient is still undergoing surgery. The low energy x-rays treat only the tumour bed to sterilise any microscopic tumour cells.
The pragmatic approach of delivering an upfront radiotherapy dose to sterilise the tumour bed avoids all the target delineation and localisation difficulties, which we face on a daily basis us-ing external beam radiotherapy.
It’s anticipated that this additional dose of IORT will help delay the tumour growing back (called local recurrence) and extend the life of patients who currently have a poor prognosis. A randomised controlled clinical trial called INTRAGO 2 has been established to answer this question.
Clinical research progress
In this clinical trial, half of patients will receive standard care and the other half will receive standard care with an additional IORT boost. This is a new technique and there were important questions to answer before launching this clinical trial to prove if an IORT boost offers benefit over standard care.
Namely the question of, if radiotherapy is delivered during surgery, how much should we deliver and what is safe to deliver? In theory, we want to deliver as much dose as possible but there are limiting factors – the impact of the dose to sensitive brain structures and also to avoid tissue necrosis.
For those who do not receive IORT in the clinical trial, an interesting and consistent fact with all clinical trial / 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.
The original INTRAGO study recruited a small cohort of patients to investigate the optimal dose to delivery during surgery. The delivered dose was escalated to three different levels and actually none of the patients reached any pre-defined toxicity levels that were concerning.
There have been attempts to introduce IORT for brain indications dating back into the early 1980s. Results have been encouraging by a number of centres, particularly in Spain and Japan. Despite this both these studies suffered from two major technical challenges:
1) To deliver radiotherapy patients needed to be transferred out of the operating theatre and into a linear accelerator bunker. This represents an infection risk in addition to the coordination difficulties.
2) The modality of radiation and technique of delivery previously used was very directional and resulted in the poor coverage of some tumour sites.
The ‘INTRABEAM’ system – a mobile miniaturised X-ray therapy unit which is not widely avail-able – addresses these areas and enables the neurosurgeons to successfully deliver IORT during surgery. This was originally developed for treating metastatic brain tumours before it gained fame in a one-shot radiotherapy solution to treat breast cancer.
There is no reason why this system cannot be used from head to toe to treat different cancer. Future technologies such as robotic-assisted surgery, virtual reality and in-room 3D surgical imaging can all be integrated with IORT to provide a versatile treatment to the radiotherapy canon in the fight against cancers.
The original brain technique involved using a single needle-shaped applicator instead of spheres and was implanted into a metastatic brain tumour (not GBMs) prior to surgical resection. Although the treatment showed good results, the popularity of stereotactic radiosurgery (performed on linear accelerators) prevented widespread uptake.
The clinical trial is likely to conclude in 2021 and success will be to promote the use of IORT as a safe and beneficial treatment that could become the gold standard in treatment for GBM.
A call for candidates
The clinical trial requires the patient to have had no previous radiotherapy or chemotherapy to treat their disease. So, it is imperative that if a patient is suspected to have a GBM that they get referred as soon as possible to be eligible for the trial. It is possible that if the patient has already undergone surgery and there is an indication for further surgery (for example, a partial resection was achieved) then, these patients may be eligible. It is imperative that the patients are referred early for treatment without already having any treatment. The early referral will best help the outcome for the patient.
Clinicians who wish to put people forward for the clinical trial can contact [email protected] Candidates must be aged 18 or older and younger than 80 and must not have had previous cranial radiotherapy.