Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy that occurs relatively rarely in childhood and young adulthood and carries a median survival of less than one year. Nevertheless, approximately 10% of patients with DIPG have been reported in the literature to experience longer survival. In a study by Lindsey F. Hoffman, University of Colorado in Denver, USA appearing in the Journal of Clinical Oncology, some characteristics that differentiate long term survivors (LTSs) from short term survivors (STSs) have been delineated.
The article describes the efforts of a large international team of investigators who reviewed the International and European Society for Pediatric Oncology DIPG Registries databases from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia to identify patients with radiographically confirmed DIPG in order to determine the clinical, radiologic, and histomolecular characteristics that contribute to long term compared with short term survival.
Of the 1,130 patients that were identified, 122 (11%) were excluded from the study. In the remaining 1,008 patients, the median age was 6.8 years (range 0 to 26.8 years). Four percent of patients were aged < 3 years at diagnosis. Of patients with available data, 755 (82%) patients presented with one or more cranial nerve palsy, or cerebellar sign, 468 (51%) presented with pyramidal tract sign, and 567 (62%) patients presented with a cerebellar sign.
Of these patients, 101 (10%) patients were determined to be LTSs indicated by survival lasting one year or more. In the LTS cohort, median survival was approximately 11 months (interquartile range 7.5 to 16 months), and the survival rate at one year was 42.3% (95% confidence interval [CI] 38.1%, 44.1%). Thereupon, survival rates in this cohort dropped considerably, with patients demonstrating 2-, 3-, 4-, and 5-year survival rates of 9.6%(95% CI 7.8%, 11.3%), 4.3% (95% CI 3.2%, 5.8%), 3.2% (95% CI 2.4%, 4.6%), and 2.2% (95%CI 1.4%, 3.4%), respectively.
Age at diagnosis, duration of symptoms and receipt of systemic therapy defined patients experiencing longer survival
Age at diagnosis turned out to be one defining factor in LTS. LTSs more often were less than 3 years of age or more than 10 years at presentation compared with STSs; 11% versus 3% were < 3 years and 33% versus 23% of were > 10 years at diagnosis, in LTSs versus STSs, respectively (p = 0.001). Longer symptom duration also was a factor in long-term versus short-term survival (p = 0.001).
Both radiotherapy and systemic therapy had been administered to 721 (74%) patients, 231 (24%) patients received only radiotherapy, and 16 (2%) patients received systemic therapy alone. In univariable and multivariable analyses, LTSs were significantly more likely to have received systemic therapy at diagnosis, 88% versus 75% STSs (p = 0.005).
The type of systemic therapy was known for 702 (70%) patients, which showed that 350 (50%) received cytotoxic therapy only, 193 (27%) patients received targeted therapy only, and 159 (23%) received both cytotoxic and targeted therapy. However, univariable analysis showed that the type of targeted therapy provided no survival difference.
Specific disease characteristics associated with shorter survival
STSs compared to LTSs, respectively, more often presented with cranial nerve palsy (83% versus 73%; p = 0.008), ring enhancement (38% versus 23%; p = 0.007), necrosis (42% versus 26%; p = 0.009), and extrapontine extension (92% versus 86%; p = 0.04).
Molecular analysis revealed that the presence of a HIST1H3B mutation favoured survival
Biopsies were performed in 299 (30%) patients, autopsies were performed in 77 (10%) patients, and 181 (48%) tumours were molecularly characterised. Biopsy specimens included glioblastoma multiforme (n = 80), anaplastic astrocytoma (n=76), anaplastic oligodendroglioma (n = 10), diffuse astrocytoma (n = 37), fibrillary astrocytoma (n = 4), oligodendroglioma (n = 2), low-grade astrocytoma (n = 8), and unknown (n = 71).
Histology of autopsy tissue included glioblastoma multiforme (n = 48), anaplastic astrocytoma (n = 12), diffuse astrocytoma (n = 3), and unknown (n = 13).
The molecular analysis illustrated that up to 90% of patients with DIPG harbour a pathognomonic point mutation in H3F3A, which was detected in 65% of tumours.
However, LTSs were more likely to harbour a HIST1H3B mutation (odds ratio 1.28, 95% CI 1.1, 1.5; p = 0.002).
The authors noted that this study, to their knowledge, represents the largest, most comprehensively annotated cohort of patients with radiographically confirmed DIPG and it confirms the relevance of some previously reported survival-associated factors in patients with DIPG.
Their study offers unique insight into patients characterised as LTSs, determining that the age at diagnosis, symptom duration, and the receipt of systemic treatment upon diagnosis improved survival.
The authors wrote that identification of survival-associated factors in this study is vital for development of prognostic subgroups and emphasizes the patient subsets that could provide the most information upon pretreatment biopsy.
Understanding biologic differences that confer survival advantage in DIPG brings clinicians closer to developing subgroup-specific therapies that, when implemented in the context of clinical trials, may improve outcomes for this devastating disease.
No external funding was disclosed.
Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, et al. Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. J Clin Oncol 2018;36(19):1963-1972. doi: 10.1200/JCO.2017.75.9308.