Exploring the potential for clinical introduction of hippocampal-sparing IMPT of pediatric medulloblastoma - Past present and future

Transcription

1 Exploring the potential for clinical introduction of hippocampal-sparing IMPT of pediatric medulloblastoma - Past present and future Daniel Gasic

2 Disclosure Nothing to disclose

3 Introduction Background Medulloblastoma Treatment Neurogensis and Neurogenic Niches (NN) Previously published articles Current studies Future perspectives

4 Background - Neurocognitive Aspects on Craniospinal Irradiation (CSI) with Protons in Pediatric MB Patients Medulloblastoma No longer classified as a Primitive Neuro Ectodermal Tumor (PNET) of the posterior cranial fossa (PCF) Standard-risk - No metastatic spread to CNS - Negative CSF cytology - Tumor size less than 1.5 cm 2 Most common PCF malignant brain tumor in children High frequency (40%) of craniospinal seeding Four different histological sub-types and two risk groups (standard- and high risk) WNT, SHH, Group 3 and Group 4 P Gibson et al Nature Dec 23; 468(7327):

5 Background - Neurocognitive Aspects on Craniospinal Irradiation (CSI) with Protons in Pediatric MB Patients Medulloblastoma Treatment; surgery, chemotherapy and CSI Favorable prognosis; 75-85% overall survival at 5 years for standard risk patients Treatment related side-effects including neurocognitive disturbances are common!

6 Background - Neurocognitive Aspects on Craniospinal Irradiation (CSI) with Protons in Pediatric MB Patients Medulloblastoma Treatment related side-effects including neurocognitive disturbances are common! Bone growth retardation Hearing loss Loss of vision Patient s suffer from generally lower IQ Gonadal dysfunction Endocrine disorders Cardio-pulmonary impairment Increased risk of stroke

7 Background - Treatment for medulloblastoma Treatment consists of: Surgery Post operative radiotherapy and vincristine chemotherapy Maintenance chemotherapy after completed radiotherapy CSI to 23.4 or 36 Gy Boost to Gy Courtesy of Dr. Patrik Brodin

8 Background - Adult Human Neurogenesis Courtesy of Dr. Thomas Björk-Eriksson

9 Background - Adult Human Neurogenesis Neurogenesis Production of new neurons Nerve impulses Regeneration of brain cells

10 Background - Neurogenic Niches (NN) and Radiosensitivity Response to ionizing irradiation of the NN (SGZ left image, SVZ right image) Sub-granular zone (SGZ) in the denate gyrus of the hippocampus Sub-ventricular zone (SVZ) of the lateral ventricles Courtesy of Dr. Malin Blomstrand, Ass. Prof. Marie Kalm and Prof. Klas Blomgren

11 Data Collection for Risk Estimation of Adverse Events After Craniospinal Photon and Proton Irradiation in Pediatric MB CSI techniques 3D-CRT RapidArc IMPT Brodin P, Munck af Rosenschöld P, Aznar M et al. Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma. Acta Oncol, 2011; 50:

12 Life years lost (LYL) estimation Brodin NP, Vogelius IR, Maraldo MV, et al. Life years lost-comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale. Cancer 2012 Apr 19.

13 Life years lost (LYL) estimation Brodin NP, Vogelius IR, Björk-Eriksson T et al. Optimizing the radiation dose prescription for pediatric medulloblastoma: Minimizing the life years lost attributable to failure to control the disease and late complication risk. Acta Oncol 2014 Apr 53(4):

14 Life years lost (LYL) estimation Brodin NP, Vogelius IR, Björk-Eriksson T et al. Optimizing the radiation dose prescription for pediatric medulloblastoma: Minimizing the life years lost attributable to failure to control the disease and late complication risk. Acta Oncol 2014 Apr 53(4):

15 Dose-response meta analysis Brodin NP, Vogelius IR, Björk-Eriksson T et al Modeling freedom from progression for standard-risk medulloblastoma: A mathematical tumor control model with multiple modes of failure. Int J Radiat Oncol Biol Phys (2):

16 Avoidance of NN with Different Radiotherapy Techniques and Neuro-cognitive Aspects on CSI in Pediatric MB Patients 3D-CRT = Conventional radiation therapy IMRT = intensity modulated radiation therapy (OAR dose 20% reduction) IMAT = intensity modulated arc therapy (OAR dose 15% reduction) IMPT = intensity modulated proton therapy (OAR dose 60% reduction) 3D-CRT IMRT IMAT IMPT Neurogenic niches Blomstrand M, Brodin P, Munck af Rosenschöld P et al. Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma. Neuro-Oncology 14(7): , 2012.

17 Avoidance of NN with Different Radiotherapy Techniques and Neuro-cognitive Aspects on CSI in Pediatric MB Patients In conclusion this in silico planning study; Possible to reduce the dose to NN in CSI with new radiotherapy techniques with potentially reduced neurocognitive side-effects (task efficiency, organization and memory) IMPT is the most effective radiotherapy technique to reduce the dose to the NN and reduce side-effects Malin Blomstrand, Patrik Brodin, Per Munck af Rosenschöld et al. Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma. Neuro Oncol Jul;14(7):882-9.

18 Dose contribution to NN with Different Radiotherapy Techniques and Neurocognitive Aspects on CSI in Pediatric MB Patients PCF boost dose contribution to NN using 3D-CRT, IMRT and IMPT Mean hippocampal dose from the boost treatment vs distance between closest point of PTV and center of hippocampus for 3D-CRT, IMRT and IMPT. The 95% prediction bounds 95% certainty for estimating dose based on this distance. A distance of >2 cm between PTV and NN there is little difference between techniques. Brodin NP, Munck af Rosenschöld P, Blomstrand M, Kiil-Berthlesen A, Hollensen C, Vogelius IR, Lannering B, Bentzen SM, Björk-Eriksson T. Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique. Neuro Oncol Apr;16(4):

19 Current studies on clinical implementation of hippocampus-sparing CSI Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Radiother Oncol May;128: Pediatric patient positioning errors Robust- and LET based optimizations

20 Current studies on clinical implementation of hippocampus-sparing CSI Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Radiother Oncol May;128: Pediatric patient positioning errors Robust- and LET based optimizations

21 Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation

22 Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Estimate radiation doses to heart and lungs using treatment information from medical records Age Gender Position Field length Field width

23 Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Various databases with long-term follow-up Adult life after childhood cancer in Scandinavia (ALiCCS) The childhood cancer survivor study (CCSS) The British childhood cancer survivor study (BCCSS) Registry for the Detection of Late Sequelae after Radiotherapy in Childhood and Adolescence (RiSK) Pediatric Normal Tissue Effects in the Clinic (PENTEC)

24 Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Fig. 1. Mean heart dose (circles) and, mean lung dose (triangles) vs. patient s age with the multivariable linear regression models. The boxplots represent the distribution of mean heart and lung doses among the 21 patients given as mean, 25th 75th percentile and range. Please note that the range of the boxplots overlap. Fig. 2. Mean heart dose (circles) and, mean lung dose (triangles) vs. spinal field width with the multivariable linear regression models. The boxplots represent the distribution of mean heart and lung doses among the 21 patients given as mean, 25th 75th percentile and range. Please note that the range of the boxplots overlap.

25 Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Provides a simple recipe for estimating doses to heart and lungs Useful tool for aiding in: Dose effect relationships Late effects in long-term pediatric cancer survivors Clinical decision making when considering competing radiation techniques Identify patients in need of closer post-treatment surveillance for late adverse effects

26 Current studies on clinical implementation of hippocampus-sparing CSI Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Radiother Oncol May;128: Pediatric patient positioning errors and techniques Robust- and LET based optimizations

27 Pediatric patient positioning errors and techniques Treatment margins (structures) NAL protocol vs. IGRT Positioning techniques

28 Pediatric patient positioning errors and techniques Courtesy of Petra Witt Nyström

29 Current studies on clinical implementation of hippocampus-sparing CSI Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation Radiother Oncol May;128: Pediatric patient positioning errors Robust- and LET based optimizations

30 Robust- and LET / RBE based optimizations LET = Linear Energy Transfer RBE = Relative Biological Effect

31 Robust- and LET / RBE based optimizations Courtesy of Dr. Alejandro Carabe-Fernandez

32 Robust- and LET / RBE based optimizations RBE varies with: Tissue specific parameters (α/β) Fraction dose (d) LET RBE for protons has been assumed to be 1.10 compared to photons Example: 1.8 Gy / fraction 23.4 Gy 1.64 Gy / fraction Gy Higher LET is more effective than lower LET

33 Robust- and LET / RBE based optimizations Courtesy of Dr. Alejandro Carabe-Fernandez

34 Robust- and LET / RBE based optimizations

35 Robust- and LET / RBE based optimizations

36 Robust- and LET / RBE based optimizations

37 Clinical Implementation of hippocampus-sparing CSI with Protons in Pediatric Patients Future perspectives on hippocampus sparing CSI with protons; Dosimetric studies Early phase II and III multicenter studies in favorable histological- and risk sub-groups in pediatric MB patients

38 Future perspectives on hippocampus sparing CSI with protons Dosimetric verification (methods) Matrix PT Film Gel dosimetry TLD Development of phantoms 3D-printing

39 Thank you Per Munck af Rosenschöld Thomas Björk-Eriksson Patrik Brodin Karsten Nysom Ivan Vogelius Søren Bentzen Marianne Aznar Maja Maraldo Malin Blomstrand Archana Singh Gautam Alejandro Carabe-Fernandez