Diffuse Intrinsic Pontine Glioma
DIPG (Diffuse Intrinsic Pontine Glioma) is a disease which strikes at the heart of childhood and it is a disease in desperate need of a cure. And at the same time, there may be no better place to start the search for a homerun cure for cancer.
DIPG affects the pons portion of the brainstem, rendering nervous system function impossible. Symptoms include double vision, inability to close the eyelids completely, dropping one side of the face, and difficulty chewing and swallowing. Unfortunately these symptoms usually worsen rapidly because the tumor is rapidly growing.
DIPG, for all its difficulties, presents an opportunity for all forms of cancer. It is one of the most resistant of all cancers to chemotherapy treatments; it affects primarily children (whose treatment has historically led to innovations in many other forms of cancer), and with a "dismal" prognosis, alternatives are few. Put together, these obstacles offer researchers a chance to revolutionize cancer research and prevention. It is even suggested that a cure to DIPG might result in a cure for almost every other type of cancer. For this reason, the cure starts now.
The Cure Starts Now strives to generate the resources necessary for doctors to study DIPG and implement the findings in hope of curing DIPG, and hopefully all cancers.
- Brain tumors are the most common solid tumor in children and comprise approximately 25% of childhood cancers 1
- Brain tumors are now the most common cancer and cause of cancer-related death in children less than 15 years of age 2
- The overall incidence rate of all primary brain tumor is 5.8 per 100,000 population in the US for children and adolescents 0-19 years of age 2
- Diffuse intrinsic pontine gliomas (DIPG) are the most common brainstem tumors in children, representing approximately 75-80% of all pediatric brainstem tumors 3
- Approximately 1504-3003 patients are diagnosed with DIPG in the USA per year.
- Median age of patient with DIPG is approximately 6-7 years 4,5
- The male to female ratio is approximately 1:11 but one publication reported a 40% Male to 60% female ratio 5
- Typical signs and symptoms include: abnormal eye movements, asymmetric smile, double vision, weakness, loss of balance, difficulty walking, clumsiness 3,4
- Symptoms are typically present for approximately a month before diagnosis, but subtle symptoms may be present for up to 6 months prior to diagnosis 3
- Diagnosis is typically confirmed by MRI. On MRI, a typical DIPG arises in the pons and takes up at least 1/2 to 2/3 of the pons, enlarges the pons and often wraps around the basilar artery.
- Routine biopsies are much more commonly done in Europe than in North America. The need for routine biopsy has been reviewed in multiple publications in recent years 6-8
- Role of Biopsy
- Historically, biopsy was done when tumors were considered not typical, were focal, or occurred in much younger or older patients.
- In recent years, multiple studies have reported that biospies can be safely done. 7,9 In the largest series, from Europe, among 130 patients who were biospsied only 3.9 % had some transient worsening of symptoms and more than 90% of patients were discharged from hospital in less than a week. 9
- Whether biopsies should be routinely done remains controversial. Material from diagnosis can provide important biological information that may delineate prognosis or help direct the type of therapy to be used.
- Mutations in DIPG
- In 2012, investigators identified a recurrent mutation in DIPGs involving two genes (H3F3A and HIST1H3B) that occurred in 85% of patients with DIPG 10-12
- This landmark finding led to the revision of the World Health Organization classification of brain tumors to include a pathologic diagnosis for tumors with imaging features of a DIPG now called a “ diffuse midline glioma, H3K27 –mutant”
- DIPGs tend to keep this and other key mutations throughout the tumor and course of the disease.8,13,14
- Standard therapy remains 3D conformal photon-based radiotherapy to a range of 54‒59.4 Gy given in 30–33 fractions of 1.8 Gy daily which prolongs survival by 2-3 months and leads to improvement in symptoms and neurological signs in the majority of patients; unfortunately the improvement is of short duration (typically months)
- Median Overall survival is < 1 year, ranging from 8-11 months 4
- 2-year survival is approximately 10% and 5-year overall survival is approximately 2%15
- Despite hundreds of clinical trials testing different chemotherapeutic agents (including targeted therapies), no agent has proven effective in this disease. 5
- Patients more likely to survive longer (i.e. more than 2 years) are those who:15
- are younger than 3 years of age or older than 10 years of age
- have fewer symptoms at diagnosis
- on MRI at diagnosis have smaller tumors, less evidence of extension beyond the pons
- are more likely to have an HIST1H3B mutation
- Pizzo, P.A., Poplack, D.G., Adamson, P.C., Blaney, S.M. & Helman, L. Principles and practice of pediatric oncology, xxiv, 1296 pages (Wolters Kluwer, Philadelphia, 2016).
- Ostrom, Q.T. et al. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol 19, v1-v88 (2017).
- Warren, K.E. Diffuse intrinsic pontine glioma: poised for progress. Front Oncol 2, 205 (2012).
- Hargrave, D., Bartels, U. & Bouffet, E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7, 241-8 (2006).
- Jansen, M.H., van Vuurden, D.G., Vandertop, W.P. & Kaspers, G.J. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev 38, 27-35 (2012).
- Kieran, M.W. Time to rethink the unthinkable: upfront biopsy of children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Pediatr Blood Cancer 62, 3-4 (2015).
- Puget, S., Blauwblomme, T. & Grill, J. Is biopsy safe in children with newly diagnosed diffuse intrinsic pontine glioma? Am Soc Clin Oncol Educ Book, 629-33 (2012).
- Cohen, K.J., Jabado, N. & Grill, J. Diffuse intrinsic pontine gliomas-current management and new biologic insights. Is there a glimmer of hope? Neuro Oncol 19, 1025-1034 (2017).
- Puget, S. et al. Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas. Childs Nerv Syst 31, 1773-80 (2015).
- Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44, 251-3 (2012).
- Wu, G. et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46, 444-50 (2014).
- Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226-31 (2012).
- Hoffman, L.M. et al. Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 4, 1 (2016).
- Nikbakht, H. et al. Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat Commun 7, 11185 (2016).
- Hoffman, L.M. et al. HG-75CLINICAL, RADIOLOGICAL, AND HISTO-GENETIC CHARACTERISTICS OF LONG-TERM SURVIVORS OF DIFFUSE INTRINSIC PONTINE GLIOMA: A COLLABORATIVE REPORT FROM THE INTERNATIONAL AND SIOP-E DIPG REGISTRIES. Neuro-Oncology 18, iii65-iii66 (2016).