and Oncology, University Medical Center Goettingen, Göttingen. Craniospinal irradiation with concurrent temozolomide and nimotuzumab in a child with.
Case study Strahlenther Onkol 2013 DOI 10.1007/s00066-013-0370-x Received: 3 March 2013 Accepted: 29 April 2013 © Springer-Verlag Berlin Heidelberg 2013
K. Müller1 · A. Schlamann1 · C. Seidel1 · M. Warmuth-Metz2 · H. Christiansen3 · D. Vordermark4 · R.-D. Kortmann1 · C.M. Kramm5 · A.O. von Bueren5 1 Department of Radiation Oncology, University Medical Center Leipzig 2 Department of Neuroradiology, University Medical Center Würzburg 3 Department of Pediatric Hematology and Oncology, University Medical Center Leipzig 4 Department of Radiation Oncology, University Medical Center Halle 5 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology
and Oncology, University Medical Center Goettingen, Göttingen
Craniospinal irradiation with concurrent temozolomide and nimotuzumab in a child with primary metastatic diffuse intrinsic pontine glioma A compassionate use treatment
Diffuse intrinsic pontine glioma (DIPG) is associated with a dismal prognosis [2] and primary metastatic disease is evident in up to 5% of patients at the time of diagnosis. Combining craniospinal irradiation (CSI) with concurrent temozolomide and nimotuzumab may potentially improve tumor control and overall survival in patients with metastatic disease. Knowledge about the feasibility and toxicity of this aggressive treatment approach is limited. A small series of 8 pediatric patients with central nervous system (CNS) embryonal tumors who received CSI (5 fractions of 3.4 Gy, 3 fractions of 36 Gy) and local boost to cumulative 54 Gy in conjunction with temozolomide (90 mg/m2/day) was presented at the 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) in June 2012. No case of severe myelotoxicity had been observed and only one patient had required packed red blood cell (PRBC) transfusion [8].
Case report An 8-year-old girl was diagnosed with a diffuse intrinsic pontine glioma with multiple spinal metastases. Within a short time, the child developed paraplegia with urinary and fecal incontinence. Given the desperate situation, the girl received craniospinal radiotherapy (total dose 35.2 Gy, single dose 1.6 Gy) and a local boost [pons: total dose 19.8 Gy, single dose 1.8 Gy; spinal deposits (thoracic vertebrae 1–8): total dose 14.4 Gy, single dose 1.8 Gy] in combination with concurrent temozolomide (75 mg/m2/day) and nimotuzumab (150 mg/m2 weekly) as an individual treatment approach on the basis of the HIT-HGG 2007 study (EudraCT 2007-000128-42) protocol of the Society of Pediatric Oncology and Hematology in Germany, Austria and Switzerland (GPOH) (. Fig. 1). Radiotherapy could be completed without interruption. However, concurrent temozolomide had to be disrupted several times due to acute myelotoxicity (grade III–IV according to
the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0). Apart from that, only lowgrade side effects (dermatitis grade I and esophagitis grade II) occurred. Maintenance immunochemotherapy could be started with a delay of 5 days and was performed according to treatment schedule. The disease could be stabilized; regrettably, an MRI scan finally depicted progression of both the pontine and spinal tumor deposits 5.7 months after the start of irradiation. The patient died 1.9 months later.
Authors’ contributions: KM was responsible for the collection of data and together with AOvB for the draft of the manuscript. CMK, HC, and DV were responsible for the treatment of the patient and the control of the documentation of the treatment and follow-up data. AOvB, AS, CS, MWM, and RDK critically evaluated and approved the manuscript. KM, AOvB, CMK, and RDK were responsible for the conception of the case report. All authors read and approved the final manuscript
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Fig. 1 8 Clinical course and treatment details shown as a flowsheet. MRI magnetic resonance imaging, TMZ temozolomide, N nimotuzumab, SD stable disease, VZ varicella zoster, PD progressive disease
Discussion The treatment of pediatric brain tumors requires a high level of expertise and an interdisciplinary treatment approach [11]. DIPG remains one of the most frustrating diseases in pediatric neuro-oncology. The standard of care is local field radiotherapy to a total dose of 54–60 Gy over 6 weeks [9]. There are solid data available that radiotherapy improves overall survival in this disease. In a pooled cohort of 97 children with large pontine gliomas who were registered in the HITGBM databases from 1983–2001 the patients who had undergone radiotherapy depicted a median overall survival of 0.87 years, whereas half of the patients who had not received irradiation died after only 0.23 years [13]. In addition, radiotherapy supports a temporary improvement in neurological function in nearly 70% of the patients [3]. In contrast, there is only little evidence supporting the use of chemotherapy in the management of DIPG. In the study performed by Wagner et al. [13], chemotherapy seemed to improve slightly the outcome as assessed by univariable analysis. This effect was still observed when the analysis was restricted to the subgroup of patients receiv-
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ing radiotherapy (1-year overall survival 45.8% vs. 34.4%, p=0.030). Frappaz et al. [5] performed frontline chemotherapy in order to delay radiation until clinical progression. Median survival increased significantly in patients who were treated according to this protocol when compared to a historical cohort of patients who underwent at least local radiotherapy though at the cost of prolonged hospitalization and an increased rate of infections. In summary the use of chemotherapy results in a marginal therapeutic benefit at best—a fact which deserves honest discussion with the children and their parents. To the best of our knowledge, this is the first report about a patient with primary metastatic DIPG who received, based on the HIT-HGG 2007 study protocol, an intensified first-line treatment by adding concurrent temozolomide and nimotuzumab treatment during craniospinal radiotherapy. Little is known about this combination in terms of toxicity and its impact on tumor control. However, given the unfavorable situation of this patient, this treatment approach appeared to be justified as a compassionate use treatment.
When the HIT-HGG 2007 study was launched in 2007, the triumph of temozolomide in the treatment of adult high-grade gliomas [12] had sparked hopes that the drug could also provide a therapeutic benefit for pediatric patients. Moreover, in all available studies the overall toxicity of a temozolomide was moderate with mostly hematological symptoms. Nevertheless, the expected payoff from temozolomide in pediatric patients with high-grade gliomas or diffuse intrinsic pontine gliomas still had to be demonstrated. Thus, the HIT-HGG 2007 study was initially designed as a clinical phase II trial to define the role of temozolomide in the first-line treatment of pediatric patients with high-grade or diffuse intrinsic pontine gliomas.
Addition of nimotuzumab immunotherapy to radiochemotherapy
In 2003, the Gilbertson’s group assessed 28 samples of diffusely infiltrating brain stem gliomas with different histopathological diagnoses (World Health Organization (WHO) grade II, n=12; WHO grade III, n=9; WHO grade VI, n=7) and demonstrated a significant increase in epidermal growth factor receptor (ERBB1/EGFR) expression in highgrade tumors (p
