Today is DIPG Awareness Day. A day that certainly deserves to be highlighted, because this type of brain cancer affects children and most of them only survive months after the diagnosis. DIPG is one of the deadliest forms of childhood cancer, with a long-term survival rate of less than 1%. There are currently very few treatments for DIPG, or Diffuse Intrinsic Pontine Glioma, which makes this aggressive brain tumour hard to cope with. Families have often limited options and limited time.

The Anticancer Fund is supporting children with DIPG and their families, as we get a lot of questions about the treatment options via My Cancer Navigator, our personal service for cancer patients.

Last year, professor David Walker joined our group of medical consultants. As an expert in DIPG, he helps us to offer the latest views on the treatment options for DIPG-patients.

In this blog, he explains his personal views on DIPG. His key message is one of lessons learned, opportunities, and hope!

A career view

As a recently retired paediatric neuro-oncologist I can look back over 40 years of experiences with children and families, facing the devastating impact of this group of diseases. On the one hand we could focus on Diffuse Intrinsic Pontine Glioma (DIPG) and its frighteningly low survival rates, the devastating progressive neurological damage and the lack of progress despite extensive trials of radiotherapy, chemotherapy and translational research. On the other hand, we could list all that we have learnt and put it into perspective for future researchers so that the experiences of the past, inform the developments of the future. I prefer the latter approach.

Anatomy and tumour pathology matter

The brainstem extends from the thalamus in the middle of the brain to the top of the spinal cord. The pons is a nerve bridge at approximately the midpoint of this span. Tumours above the pons are either called “thalamic” or “midbrain” tumours. Those involving the pons are referred to as “pontine” and those arising in the brainstem below the pons are called “medullary”. When the tumours are astrocytic type and in these locations they constitute “Midline Gliomas”. Their imaging appearances vary; some are “intrinsic”, growing within the brainstem structures; some grow out from the brainstem and referred to as “exophytic”. Some are “diffuse”, merging without boundaries into brain structures; others are “focal”, forming nodules or cysts.

Pathologically some are considered benign / grade 1, typically characterised as pilocytic histology with a variety of BRAF mutations, some of which are targetable by drugs. They grow slowly and spontaneously stop their growth when adolescence ends. Others are malignant / high grade, they continue to grow, invade and spread within the brainstem and the rest of the central nervous system causing progressive disability and almost inevitable death. An exciting recent discovery has linked the h3K27M histone mutation to a new combined anatomical category of malignant diffuse midline glioma.

Taken together these descriptive characteristics matter as they determine the surgical approaches that are possible to sample tumour tissue, drain cysts, remove tumour nodules or exophytic growths, infuse drugs to tumour within or on the surface of the brain or direct ultrasound to disrupt the blood brain barrier to enhance drug penetration. The grading of “benign” versus “malignant” and “molecular” typing helps predict tumour behaviour and is being used to select drugs and delivery techniques to target tumour growth mechanisms in different anatomical locations in clinical trials.

Currently effective therapies

As a clinician, the most important lesson I have learnt is that the tumours in this location threaten life and disability by interfering with the brainstem’s life-preserving functions of breathing, swallowing, mobility and cardiac function. For focal and exophytic tumours, surgical resection is often possible and can be dramatic in its impact on symptoms, especially in grade 1 tumours. Diffuse tumours are not surgically removable and are considered malignant and are treated with radiotherapy, to which they are only partially sensitive.

Radiotherapy in the Diffuse Midline Glioma is considered temporarily palliative and can be used more than once, but with increasing risk of irreversible local brainstem damage with each treatment. Steroids remain almost the only effective drug treatment to control symptoms, which they do, by reducing the effects of brain swelling on brainstem function. Their continuous use in children, however, is associated with disturbing side effects on appetite, endocrine function, leading to weight gain, behavioural disturbance and can cause distressing disfigurement of appearance and reduced mobility due to muscle wasting. Steroid dosing strategies, if adopted, can be very effective in reducing these side effects.

Other anti-angiogenic drugs, such as Bevacizumab, can preserve neurological function, with fewer side effects. Neither of these drugs treat the tumour itself. They do preserve brainstem function, which is, in itself, life-preserving and offers control of neurological deterioration, at a cost. Survival rates range from over 50% 5 year survival to less than 10% 5 year survival. The differences are related to characteristics I have described. The best outcomes are for children amenable to tumour resection with low grade tumours and the poorest survival is for the diffuse intrinsic pontine glioma.

Targeting the tumour with novel drug and delivery strategies is now possible.

The stage is uniquely set for a new range of treatment trials in this group of diseases as the surgical and radiotherapy strategies are established and their effects understood. Cytotoxic drugs, given systemically and in combinations at maximised doses, have not to-date produced any measurable benefit, perhaps because they do not penetrate the blood brain barrier (BBB).

A new set of strategies are being applied, using anatomically and biologically targeted approaches to selecting drugs for their capacity to act on specific mechanisms and their capacity to penetrate or bypass the BBB by drug design or delivery techniques such as:

• drugs with lipid solubility characteristics
• convection enhanced drug delivery (CED),
• ultrasound blood brain barrier disruption (USS BBBD),
• intra-CSF delivery,
• intra-arterial therapy
• immunological targeting
• transmucosal delivery
• electric field therapy

These offer innovation of effect and greater certainty as to the drug / treatment’s delivery to the tumour and brain tissues, whilst minimising systemic doses and associated side effects. Creating a rationale for prioritisation of drugs / treatments in combination with a delivery system for such trials is an essential step to avoid wasteful repetition and illogical selection. Designing a total treatment programme, combining technical elements of therapy, and its delivery, with synergistic actions aimed at prolonging life and avoiding disability is a key objective.

International research cooperation poses challenges and offers great hope

Perhaps the greatest hope for the future lies in the international collaboration that now exists between translational researchers to develop and test these new ideas. The pressure from distressed parents to try anything to save their child is a powerful motivation and an ethical challenge to all who work in the field. The impact of “hope” with any new treatment, raises expectations for distressed families, who feel that they have very limited time with their ill child and that anything is worth trying, at any expense. The clinical, scientific and ethical challenges in this rare condition of children means that:

• there are conflicts about prioritising which treatment to try next and in what combination;
• there is a need to adopt trials with recognised methods, approvals and timelines;
• there is a need to support collaboration between academic and commercial groups;
• there is a need to record any innovative experience and share it with the clinical and scientific community;
• there is a need to sustain engagement with the families who have had experience and support the new families facing the diagnosis;
• there is a need to recognise that individual families have the right to make their choice for therapies for their children;
• all practitioners must practice within the national professional regulations and international ethical guidance;
• there is a need to prioritise investment into children’s brain tumour translational research despite their commercial reputation as a “Cinderella specialty”.

What does the future hold?

These challenges offer “Moonshot Moment(s)” to those brave enough to develop integrated, adaptable approaches to innovation, designed for their unique clinical and neuro-scientific characteristics. Other childhood cancers have been cured with total treatment programmes, using combined approaches. Real progress in this arena will permit so much more to be learnt. The personal, clinical and commercial rewards could be exceptional.

It has been my experience and privilege to witness extraordinary examples of support from the children and their families to encourage translational research in this arena. They are waiting for progress to be announced. They are willing to support innovation and collaboration. It is up to the clinician scientists to generate the opportunities the children deserve.