A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high‐grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study

Abstract

Background Diffuse intrinsic pontine gliomas (DIPG) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. Methods Eligible patients age 3–21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily × 5 for two weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was to be considered promising if the patients with one-year PFS for DIPG and HGA was at least 6 of 25 and 14 of 26 patients respectively. Results Forty-five evaluable patients were enrolled (25 DIPG, 20 HGA). Six patients with DIPG patients and five with HGA patients were progression-free at 1 year from the start of therapy with one-year progression-free survivals of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally grade 1 and 2. Increased EGFR copy number but no K-ras mutations were identified in available samples. Conclusions The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, OS was not markedly improved from historical controls therefore does not merit further study in this population.

Surveillance imaging for high‐grade childhood brain tumors: What to do 10 years after completion of treatment?

“…4,32,33 According to data from four consecutive German HGG protocols, about 3% have initial metastatic disease. 34 The rate of progressive disease after 1 year was 75% in the study from Macy et al 35 The event-free survival after 1 year was higher (43%) according to Wolff et al 36 The 5-year event-free survival in this cohort was 13%. Table 2 summarizes the most important findings from eligible studies on SMN, IVM, and white matter lesion (WML).…”

“…We found no recurrence of the primary brain tumor, either local or distant, 10 years or more after the end of treatment in the reviewed literature . After combining the latency period from all relapses, median time to relapse was 13.7 months; average minimal latency time was 3.3 months and a maximum of 49.0 months.…”

“…The rate of progressive disease after 1 year was 75% in the study from Macy et al . The event‐free survival after 1 year was higher (43%) according to Wolff et al .…”

Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review

“…However, upfront radiation appears to only provide transient relief of symptoms while offering minimal survival advantage. Studies examining the role of alternative fractionation regimens and/or addition of radiosensitizers have failed to demonstrate a survival benefit 10, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. The median overall survival (OS) for this unique patient population remains approximately 10 months 34 …”

Gliomas in Children

“…Many trials over the last few decades have tried different drugs and drug combinations for adjuvant chemotherapy, including temozolomide (TMZ), pCV (prednisone, lomustine [CCNU], vincristine), bevacizumab, irinotecan/cetuximab, and others, but have not been able to show survival benefits beyond radiotherapy alone, whereas some regimens added substantial toxicity. [48][49][50][51][52] Even higher doses of radiotherapy (70-78 Gy given in a hyperfractionated regimen) failed to prolong survival but increased neurotoxicity. 53,54 However, efforts to re-irradiate children with DIPG at first and even second progression have recently gained popularity and have led to clinical improvements and median survival increases of a few months without adding significant toxicity.…”