Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy – Results of a United Kingdom phase II trial (CNS 2007 04)

Abstract

Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28 d) of temozolomide was studied with the aim of overcoming O6-methylguanine methyltransferase (MGMT) mediated resistance.Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m2) after which up to 12 courses of 21 d of adjuvant temozolomide (75–100 mg/m2) were given 4 weekly. The trial used a 2-stage design and passed interim analysis.At diagnosis median age was 8 years (2–20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10–100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5–11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis.This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.

Pediatric Brainstem Gliomas: A Retrospective Study of 180 Patients from the SEER Database

“…While the search for novel pharmaceuticals is still ongoing, biological agents that target various molecular pathways and immunological processes have shown promise in the treatment of these difficult to treat and deadly neoplasms. Various studies have looked into the efficacy of bevacizumab, metronomic therapy, lenalidomide, and temozolomide; however, these have been conducted in primarily low-grade gliomas without predication for pediatric and adult populations [39-42]. Temozolomide, which has been used in various adult intracranial neoplasms, has not shown the same results in pediatric patients [42, 43].…”

Radiation Therapy and Nimotuzumab in Children and Adolescents with Brainstem Gliomas: A 5-Year Institutional Experience

“…1,3,5,12,[28][29][30][31][32][33][34] In a previous case series of patients treated only with RT during the period 1992-2008 in the same Institution (National Oncology and Radiobiology Institute, in Havana), median survival time was 10.0 months and the survival rate at 2 years was 15%. We know that the use of retrospective case series as control groups have limitations, but there are facts that are relevant: all cases were irradiated in the same Institution, so there could not exist center-effects that could bias patient groups.…”

“…[1][2][3]5,12,21 Radiation dose escalation increases toxicity but does not improve outcome; neither chemotherapy nor hypofractionation 4,21-24 have improved therapeutic ratio.…”

“…The association of Chemotherapy (ChT) and radiotherapy (RT) have not improved survival 1,[6][7][8]10,11 and now biologics are combined with RT in clinical trials. 9,12,13 We investigated the association of RT with Nimotuzumab, a humanized monoclonal antibody developed at the Center of Molecular Immunology, Havana, Cuba and testing the hypothesis that this combination will improve survival in these tumors.…”

“…The brainstem is defined as the midbrain, pons and medulla; brainstem gliomas are generally diffuse intrinsic tumors involving the pons, with defined clinical presentation and characteristic appearance in imaging findings and do not require pathological confirmation; [1][2][3][4] it can extend along neural tracts to adjacent regions of the brain, so it has been defined as fatal disease. Radiation treatment response rates show low degrees of efficacy, with short-term responses and a median overall survival less than one year; [2][3][4][5][6][7][8] Diffusely infiltrating pontine glio-mas must be distinguished from other subsets of diffuse intrinsic pontinegliomas, such as focal tumors, which are described with better prognosis and longer term survival.…”