Pediatr Blood Cancer
Radiation Therapy and Concurrent Topotecan Followed by Maintenance Triple Anti-Angiogenic Therapy With Thalidomide, Etoposide, and Celecoxib for Pediatric Diffuse Intrinsic Pontine Glioma
1 2 3 4 Mikaela Porkholm, MD, Leena Valanne, MD, PhD, Tuula Lo¨nnqvist, MD, PhD, Stefan Holm, MD, 5 6 7 8 Birgitta Lannering, MD, PhD, Pekka Riikonen, MD, PhD, Dorota Wojcik, MD, PhD, Astrid Sehested, MD, 9 10 11 12 Niels Clausen, MD, Arja Harila-Saari, MD, PhD, Eckhard Schomerus, MD, Halldora K. Thorarinsdottir, MD, 13 14 15 1 Pa¨ivi La¨hteenma¨ki, MD, PhD, Mikko Arola, MD, PhD, Harald Thomassen, MD, Ulla M. Saarinen-Pihkala, MD, PhD, 1 and Sanna-Maria Kivivuori, MD, PhD *
Background. Despite major treatment attempts, the prognosis for 61% and 17%, respectively. The median overall survival was pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. 12 months (range 4–60 months). Four radiological complete Gliomas are highly vascularized tumors, suggesting that the responses were seen, of which two were transient. Radiologically, prevention of vessel formation by anti-angiogenic treatment might 56% of the tumors reduced in size and 78% in signal intensity. Study be effective. Procedure. Forty-one pediatric patients with DIPG were patients were able to visit school or daycare and walk for a treated according to the Angiocomb protocol, starting with significantly longer time compared to controls (Log Rank 0.036 and radiotherapy combined with topotecan and followed by anti- 0.008, respectively). Adverse effects were generally minor. Con- angiogenic triple medication consisting of thalidomide, etoposide, clusions. The Angiocomb protocol created a noticeable share of and celecoxib. Overall survival, radiological response, quality of life, long-term survivors and was well tolerated, suggesting that anti- requirement of corticosteroids, and adverse effects were monitored. angiogenic therapy for patients with DIPG should be studied more in Eight patients treated with only radiotherapy were used as controls. the future. Pediatr Blood Cancer # 2014 Wiley Periodicals, Inc. Results. For study patients, the 12 and 24 months overall survival was
Key words: anti-angiogenic therapy; celecoxib; etoposide; pediatric; pontine glioma; thalidomide
INTRODUCTION in the analysis of the topotecan effect and toxicity but excluded from the other analyses. One patient with DIPG both radiologically Brain tumors are the most common solid malignancies of and histologically treated according to the Angiocomb protocol was childhood [1]. Twenty percent arise from the brainstem, and of excluded from all analyses due to an atypical clinical picture prior these, diffuse intrinsic pontine gliomas (DIPGs) account for the to diagnosis. This patient is included in the adverse effect report. largest share [2]. Despite major treatment attempts, the prognosis for DIPG still remains poor and most patients die within a year of 1 diagnosis [2]. Division of Hematology-Oncology and Stem Cell Transplantation, Gliomas are known to be densely vascularized tumors and very Children’s Hospital, Helsinki University Central Hospital, Helsinki, Finland; 2Helsinki Medical Imaging Center, Helsinki University dependent on angiogenesis [1,3]. Suppression of blood vessel Central Hospital, Helsinki, Finland; 3Division of Child Neurology, growth by anti-angiogenic drugs might therefore be effective in the Helsinki University Central Hospital, Helsinki, Finland; 4Department treatment of DIPGs. In addition to being important for tumor of Pediatric Hematology-Oncology, Astrid Lindgren Children’s growth, blood vessels also give rise to drug resistance [4], since the Hospital, Karolinska University Hospital, Stockholm, Sweden; 5De- blood–brain barrier prevents chemotherapeutic agents from partment of Pediatric Hematology-Oncology, The Queen Silvia penetrating from the bloodstream to the site of action [4–6]. Children’s Hospital, University of Gothenburg, Gothenburg, Sweden; Anti-angiogenic treatment targets the tumor vessel walls and does 6Department of Pediatrics, Kuopio University Hospital, Kuopio, 7 8 not require penetration of the blood–brain barrier [7]. Angiogenesis Finland; Haukeland University Hospital, Bergen, Norway; Depart- ment of Pediatric Hematology/Oncology, Rigshospitalet, Copenhagen, can be inhibited by metronomic administration of drugs, meaning 9 oral, long-lasting dosing without breaks [8–10]. Denmark; Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark; 10Pediatric Oncology/Hematology Section, Depart- From these findings, the Angiocomb protocol for treatment ment of Pediatrics, Oulu University Hospital, Oulu, Finland; of brainstem gliomas was developed. Preliminary results from 11Department of Pediatric Hematology and Oncology, H. C. Andersen the Angiocomb pilot study were encouraging: the overall survival Children’s Hospital, Odense University Hospital, Odense, Denmark; (OS) 12 months from diagnosis was 63% and the quality of life 12Pediatric Hematology-Oncology, The Children’s Hospital, Reykja- was remarkably better compared to controls treated with only vik, Iceland; 13Department of Pediatrics, Turku University Central radiotherapy [11]. Hospital, Turku, Finland; 14Department of Pediatrics, Tampere University Central Hospital, Tampere, Finland; 15Trondheim Universi- PATIENTS AND METHODS ty Hospital, Trondheim, Norway Conflict of interest: Nothing to declare. Patients Correspondence to: Sanna-Maria Kivivuori, Children’s Hospital, Altogether 45 patients with DIPG were recruited consecutively Helsinki University Central Hospital, POB 281, FIN-00028 Helsinki, in 13 centers in all five Nordic countries. From this group, two Finland. E-mail: sanna.kivivuori@iki.fi patients treated with only radiotherapy and topotecan were included Received 26 November 2013; Accepted 5 March 2014