A Roadmap to Find a Cure for Glioblastoma
A submission to the government’s consultation for the national cancer plan
Introduction
Glioblastoma is a diagnosis of terminal brain cancer where there has been no change in treatment in 20 years. People diagnosed with glioblastoma have been left behind in the great advances in cancer diagnosis and treatment. We are suggesting focused and achievable actions that can be implemented to start on the journey to redress this imbalance. These actions will lead the way to improvements for people diagnosed with brain cancer and support improvements for others diagnosed with the left-behind cancer diagnoses. The aim of ‘Change NHS’ is to help build a health service for the future. As part of this the Department of Health and Social Care has a mission goal to reduce lives lost to the biggest killers. Although the incidence of glioblastoma makes it a rare cancer, there have been no new treatments for 20 years and as a result, glioblastoma is one of the biggest killers.
Background to Glioblastoma
Glioblastoma is the most common malignant primary brain tumour with an incidence of 3‐4/100,000, accounting for approximately half of all malignant primary brain tumours. There are approximately 2,200 new cases diagnosed annually in England (Brodbelt et al., 2015). Glioblastoma is highly infiltrative and rapidly progressive. Median survival of patients with newly diagnosed glioblastoma is 14.6 to 21.1 months when receiving standard therapy in clinical trials (Chinot et al., 2014; Gilbert et al., 2014; Johnson et al., 2012; Malkki et al., 2016; Stupp et al., 2009; Stupp et al., 2015). However, overall survival from registry databases is only 6‐10 months (Brodbelt et al., 2015; Ostrom et al., 2015, Brown et al., 2022).
Figure 1
Kaplan−Meier survival estimate of overall survival. Real-world experience; data from review of 490 consecutive patients diagnosed at the National Hospital for Neurology and Neurology from January 2011 to December 2015. The average survival of patients was 9 months. There has been no change in treatment since this cohort was diagnosed (Brown et al. 2022).
Patients with glioblastoma can present with various symptoms that represent focal neurology, raised intracranial pressure, or diffuse infiltrative disease. Typical presentations include headache, seizures, focal neurological deficits, confusion, memory loss, and personality changes (Wen et al., 2008). MRI incorporating T1 sequences with and without contrast, T2‐ and FLAIR‐ sequences is standard for radiological diagnosis of glioblastoma (Ellingson et al., 2015). Patients generally present to Accident & Emergency, through the GP or specialist neurology. Tissue diagnosis follows the WHO Classification that defines tumours based on both histology and molecular characteristics (including MGMT promotor methylation status and IDH‐1 mutation status), and integrates tumour type and grade (Weller et al., 2017; Louis et al., 2016).
Current Standard of Care for Glioblastoma
Initial management following radiological diagnosis or biopsy is surgical debulking, if possible. Surgery is both diagnostic and therapeutic, and intends to remove as much of the tumour as possible without significantly risking neurological impairment (Weller et al., 2017). There remains an absence of prospective clinical trial data in defining correlation of extent of surgery and prognosis (Hess, 1999). However, systematic reviews support that extent of resection correlates with prognosis (Sanai et al., 2008; Almenawer et al., 2015; Brown et al., 2016). If debulking surgery is not feasible, a biopsy is performed for diagnostic purposes.
Surgery is followed by adjuvant chemoradiotherapy as the current standard of care for newly diagnosed glioblastoma (Stupp et al., 2014; Weller et al., 2017). 60 Gray (Gy) of fractionated focal external beam radiotherapy is delivered in 30 x 2 Gy fractions over six weeks. Daily concomitant temozolomide 75mg/m2 is given alongside this. Following a 4-week break post-radiotherapy, six cycles of adjuvant temozolomide 150‐200mg/m2 are delivered for five days (days 1 to 5) in a 28-day cycle.
The current standard of care was implemented approximately 20 years ago following the results of an EORTC‐NCIC randomised phase III trial that demonstrated a 2.5-months improvement in median survival with radiotherapy with concomitant and adjuvant temozolomide over radiotherapy alone in patients with newly diagnosed glioblastoma (Stupp et al., 2005; Stupp et al., 2009). Recently, the addition of tumour treating fields following chemoradiotherapy has shown prolonged survival in a preliminary analysis of a phase III trial, but this treatment has yet to be widely implemented (Stupp et al., 2015).
In older patients and those with a poor performance status who are not expected to tolerate standard therapy, treatment options include hypo-fractionated radiotherapy with or without temozolomide chemotherapy, temozolomide chemotherapy alone, or best supportive care (Stupp et al., 2014; Weller et al., 2017).
Almost all patients relapse after initial treatment. No accepted standard of care exists for relapsed glioblastoma, and no treatment has been demonstrated to significantly prolong survival following relapse in randomised clinical trials. Pharmacological options include nitrosourea based regimens, temozolomide re‐challenge, or bevacizumab (off‐label). Bevacizumab prolongs progression‐free survival but does not confer a survival advantage and is not licensed for use in glioblastoma within the EU and the UK. Typical nitrosourea based regimens are lomustine monotherapy or combination PCV (procarbazine, lomustine [CCNU], vincristine) (Stupp et al., 2014; Weller et al., 2017).
Early Diagnosis/ Treatment/ Research and innovation
Currently a patient is diagnosed with glioblastoma after they have had a biopsy of the tumour or they have had surgery to reduce the tumour bulk and neuropathology has confirmed it is glioblastoma. This could be 8 weeks or more since their MRI head with contrast showing the tumour. In the great majority of cases, in that time, the neuro-oncology multidisciplinary team know that the diagnosis is glioblastoma. This prevents change in treatment, as part of innovation will come from giving patients treatments earlier in their treatment pathway in clinical trials.
Evidence for preventing change comes from the failure to recruit of the clinical trial ‘A Phase II Trial of Neoadjuvant Therapy in Patients with Newly Diagnosed Glioblastoma’, Clinical trials.gov NCT05074992, Sponsor UCL, Funder Jon Moulton Charity Trust. This trial was for people who are newly diagnosed and were due to be given immunotherapy prior to surgery and standard treatment to prime the immune system. The trial only recruited one patient and was closed due to not meeting recruitment targets despite being offered to 20 neuro-oncology centres in the UK. The patient is alive and well, 2 ½ years after diagnosis.
There is a clear lack of clinical trial opportunities for people diagnosed with glioblastoma. The transformation in other cancers from terminal illness to disease control and cure has come from clinical trials. The pharmaceutical industry needs encouragement and support to invest in new treatments for glioblastoma, a relatively rare where it is difficult to make a business case. Baroness Margaret McDonagh started a campaign to improve access to clinical trials for glioblastoma brain cancer patients, with the aim of finding a cure. Her sister, Dame Siobhain McDonagh MP has taken on this campaign and we are due to open the first of Margaret’s trials in July 2025.
The Glioblastoma Campaign has five steps to finding a cure
Earlier diagnosis leading to earlier and better treatment
Bring together a panel of experts to arrive at a consensus about how and when we can diagnose glioblastoma with imaging alone.
In the great majority of cases, the neuro-oncology multidisciplinary team know from the MRI scan that the diagnosis is glioblastoma. This MRI diagnosis usually comes 8 weeks or more before confirmatory diagnosis by surgery, which allows treatment to commence sooner.
Given that the developing treatments are based on administering immunotherapy drugs ahead of surgery, earlier MRI diagnosis would enable improvements to treatments and thus success rates.
There will be a false positive rate from MRI scans, and we would need to understand what that rate would be, and what would be the implications of starting a treatment in these instances, as part of the consensus-forming exercise.
New technology is evolving and the possibility of diagnosing glioblastoma from a blood test is coming closer. Pilot studies about this could be supported and this information integrated with the imaging into making the diagnosis.
Providing a pipeline for more clinical trials
A public/private partnership for clinical trials for rare cancers
Clinical trials are hugely expensive for pharmaceutical companies to run without an expectation that there will be a significant return on the investment for many of those trials. By their very nature, rare cancers are much less likely to provide sufficient return, meaning pharmaceutical companies are more unwilling to run them, meaning there are fewer clinical trials for rare cancer drugs.
With a commitment to ‘No cancer left behind’ the NHS can partner with private companies to make sure that new or repurposed drugs are trialled for all cancers, sharing the early risks across public and private sectors. The NHS should run the trials, and the drug companies should be expected to provide the drugs.
We request that the DHSC directly support a test case project for glioblastoma treatments to develop a strategy with AstraZeneca, a global leader in Life Sciences who has set up a rare cancers unit, for shared trials.
Keeping costs down
Provide automatic NIHR badging for rare cancer drug trials
Costs are always a barrier to most drug trials. However, trials conducted under the auspices of the National Institute for Health and Care Research (NIHR) are always conducted at reduced rates.
So to keep down the costs of trials into drugs for rare cancers, they should be automatically considered to be NIHR-badged. This will give access to NHS resources for all funded studies in glioblastoma and other left-behind cancers.
An inclusive policy for rarer cancers
Review the mission statement and objectives of the Medicines and Healthcare products Regulatory Agency (MHRA)
The current mission statement and objectives of the Medicines and Healthcare products Regulatory Agency (MHRA) is not inclusive nor supportive to people with left-behind cancers.
For example, when a drug is being prepared for a submission for review to the MHRA, all data needs to be considered in the application, no matter what cancer the data relates to. This acts as a disincentive to trial existing drugs on other, rarer cancers, just in case it doesn’t work for them and thus drags the overall data down. Drug companies are reluctant to do this with drugs in use for the common cancers because it impacts negatively on their primary therapeutic use.
The MHRA should, instead, consider each drug in respect of its efficacy for each cancer in isolation instead of lumping the data for the drug across all cancers. So the same drug trialled for use on both lung cancer and on glioblastoma, for example, should be assessed separately for each cancer, and should be licensed or not based on the data for each specific cancer. This would permit the pharmaceutical industry to support research programs for rare cancers.
Providing existing drugs for trials
Being deliberate about finding which existing drugs can be used to treat rarer cancers
The Medicines Repurposing programme in NHS England has been set up to “identify and progress opportunities to use existing medicines in new ways.”
The programme currently has three aims, which are to:
identify and develop opportunities to repurpose prioritised medicines to improve outcomes, patient experience and value for money.
support and advance innovative research into medicines that might be repurposed and adopted into the NHS.
facilitate and encourage the licensing of repurposed medicines to support clinical decision making and improve equity of access.
There should be a fourth, very specific aim added to these three general ones, which is to ensure the supply of existing drugs for clinical trials into whether they can be repurposed for the treatment of glioblastoma and other rare cancers.
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