Proton Therapy for Ependymoma and Craniopharyngioma at the University of Florida: Lessons Learned About Efficacy and Toxicity

Transcription

1 Proton Therapy for Ependymoma and Craniopharyngioma at the University of Florida: Lessons Learned About Efficacy and Toxicity Danny Indelicato, MD Mendenhall Chair of Pediatric Radiotherapy University of Florida

2 Disclosure I will not be discussing any specific pharmaceutical or hardware company

3 Lesson #1 Proton therapy is broadly accepted and widely utilized in the treatment of ependymoma and craniopharyngioma in the United States and Europe

4 Participants responses to the question: What is the treatment of choice for the following pediatric tumors? Participants could answer proton therapy, photon therapy, or both, depending on circumstances. 2016

5 2016 Worldwide Proton Therapy Delivery Top 10 diagnoses (75% of patients) All countries USA EUR ASIA Rhabdomyosarcoma 244 (13.4) 162 (13.4) 52 (12.0) 30 (16.8) Medulloblastoma 230 (12.7) 149 (12.4) 59 (13.7) 22 (12.3) Ependymoma 205 (11.3) 131 (10.9) 62 (14.4) 12 (6.7) Low-grade glioma 129 (7.1) 93 (7.7) 25 (5.8) 11 (6.1) Ewing sarcoma 125 (6.9) 91 (7.6) 27 (6.3) 7 (3.9) Neuroblastoma 103 (5.7) 57 (4.7) 13 (3.0) 33 (18.4) Craniopharyngioma 100 (5.5) 61 (5.1) 34 (7.9) 5 (2.8) Intracranial pure germinoma 86 (4.7) 52 (4.3) 19 (4.4) 15 (8.4) Hodgkin lymphoma 80 (4.4) 77 (6.4) 1 (0.2) 2 (1.1) Other bone/soft tissues sarcoma 73 (4.0) 46 (3.8) 23 (5.3) 4 (2.2) Journy N, Indelicato DJ, Klinerman R, Withrow D, de Gonzalez

6 children treated at UF since Over 200 ependymomas and craniopharyngiomas

7 Pubmed accessed on August 30, 2018 Articles involving craniopharyngioma (42) or ependymoma (67) proton radiation : 109 craniopharyngioma (14) or ependymoma (18) IMRT radiation : 32 craniopharyngioma (10) or ependymoma (13) proton radiation outcome : 23 craniopharyngioma (4) or ependymoma (4) IMRT radiation : 8 Both the largest series describing the outcome of radiotherapy for pediatric ependymomas and craniopharyngiomas were carried out with protons

8 Lesson #2 In ependymoma, proton therapy and limited CTV margins reduce the radiation dose to developing neural tissue without compromising disease control Proton plan IMRT plan

9 Patient Characteristics 179 pediatric patients with non-metastatic intracranial ependymoma treated between on prospective outcome study 98 patients (55%) were 3 years old 103 patients (58%) were male 119 patients (65%) had posterior fossa tumors 120 patients (67%) had grade 3 tumors

10 Pre-radiation treatment 152 patients (85%) had total or near total resection prior to RT 48 patients (27%) required more than 1 resection 59 patients (33%) received pre-rt chemotherapy 36 patients (20%) with methotrexate-based regimen Median duration between definitive surgery and radiation was 55 days in patients who did not receive chemotherapy

11 University of Florida Ependymoma Treatment Guidelines GTV = Tumor bed and any residual disease

12 University of Florida Ependymoma Treatment Guidelines GTV = Tumor bed and any residual disease CTV1 = GTV + 5 mm

13 University of Florida Ependymoma Treatment Guidelines GTV = Tumor bed and any residual disease CTV1 = GTV + 5 mm PTV1 = CTV1 + 3 mm

14 University of Florida Ependymoma Treatment Guidelines GTV = Tumor bed and any residual disease CTV1 = GTV + 5 mm PTV1 = CTV1 + 3 mm CTV2 = GTV

15 University of Florida Ependymoma Treatment Guidelines GTV = Tumor bed and any residual disease CTV1 = GTV + 5 mm PTV1 = CTV1 + 3 mm CTV2 = GTV PTV2 = CTV2 + 3 mm

16 Prescription Dose University of Florida Ependymoma Treatment Guidelines * If 3 y/o with a gross total resection, no PTV2 boost PTV2 = 59.4 Gy PTV1 = 54 Gy

17

18 100 Median follow-up: 3.2 years Patients lost to follow-up: 2 Freedom from event (%) Overall survival (3 yr: 90.4%) Local control (3 yr: 85.4%) Progression-free survival (3 yr: 75.9%) Years

19 Literature Review: Pediatric Ependymoma Group Author (year) N 3 yr LC 3 yr PFS 3 yr OS Current Study Indelicato (2017) % 76% 90% Historic UF Swanson (2011) 25 31%* 25%* 35%* *10 year

20 Literature Review: Pediatric Ependymoma Group Author (year) N 3 yr LC 3 yr PFS 3 yr OS Current Study Indelicato (2017) % 76% 90% Historic UF Swanson (2011) 25 31% 25% 35% CHOP Kuo (2007) 49 NR 41%* 66%* WashU** Mansur (2005) 40 NR 58%* 71%* Taiwan Jiang (2004) 31 NR 52%* 58%* Iowa Paulino (2002) 28 65%* NR 86%* Kyoto** Oya (2002) 48 NR 42%* 62%* Rotterdam Van Veelen-Vincent (2002) 44 NR 64%* 80%* ** includes adult patients * 5 year

21 Literature Review: Pediatric Ependymoma Group Author (year) N 3 yr LC 3 yr PFS 3 yr OS Current Study Indelicato (2017) % 76% 90% Historic UF Swanson (2011) 25 31%* 25%* 35%* CHOP Kuo (2007) 49 NR 41%* 66%* WashU** Mansur (2005) 40 NR 58%* 71%* Taiwan Jiang (2004) 31 NR 52%* 58%* Iowa Paulino (2002) 28 65%* NR 86%* Kyoto** Oya (2002) 48 NR 42%* 62%* Rotterdam Van Veelen-Vincent (2002) 44 NR 64%* 80%* Historic Average Various % 25-64% 35-86% ** includes adult patients * 5 year

22 Literature Review: Pediatric Ependymoma Group Author (year) N 3 yr LC 3 yr PFS 3 yr OS Current Study Indelicato (2017) % 76% 90% Historic Average Various % 25-64% 35-86% St Jude Merchant (2007) %** 69%** 81%** ** 7 year

23 Literature Review: Pediatric Ependymoma Group Author (year) N 3 yr LC 3 yr PFS 3 yr OS Current Study Indelicato (2017) % 76% 90% Historic Average Various % 25-64% 35-86% St Jude Merchant (2007) % 69% 81% PSI Ares (2016) 50 86% NR 88% MGH MacDonald (2013) 70 83% 76% 95%

24 Literature Review: Pediatric Ependymoma Group Author (year) N 3 yr LC 3 yr PFS 3 yr OS Current Study Indelicato (2017) % 76% 90% Historic Average Various % 25-64% 35-86% St Jude Merchant (2007) % 69% 81% PSI Ares (2016) 50 86% NR 88% MGH MacDonald (2013) 70 83% 76% 95% AIEOP Massimino (2016) %* 65%* 81%* French Child s Cancer Society Ducassou (2015) % 53-62% 77-86% CCG/COG Garvin (2012) 84 NR 57%* 71%* * 5 year

25 Lesson #3 Treatment technique and risk factors impact ependymoma control these are applicable beyond particle therapy

26 Variable Age at RT Age at first surgery Gender Grade Recurrent prior to RT Race Chemotherapy prior to RT GTR/NTR at time of radiation 3 Year Disease Control Estimates on Univariate Analysis N Local Control (%) P= Progression- Free Survival (%) P= Overall Survival (%) % 77% 91% > % 74% 90% % > % 78% 72% 90% 91% Female 76 92% 87% 99% <0.05 Male % 67% 84% % 81% 90% % 73% 91% Yes 18 93% 84% 100% No % 75% 89% White/Asian % 78% 92% Black/Hispanic 26 80% 64% 81% Yes 59 87% 75% 87% No % 76% 92% Yes % 79% 93% <0.01 <0.05 No 27 67% 59% 77% P= <0.01 <0.05

27 Variable Age at RT Age at first surgery Gender Grade Recurrent prior to RT Race Chemotherapy prior to RT GTR/NTR at time of radiation 3 Year Disease Control Estimates on Univariate Analysis N Local Control (%) P= Progression- Free Survival (%) P= Overall Survival (%) % 77% 91% > % 74% 90% % > % 78% 72% 90% 91% Female 76 92% 87% 99% <0.05 Male % 67% 84% % 81% 90% % 73% 91% Yes 18 93% 84% 100% No % 75% 89% White/Asian % 78% 92% Black/Hispanic 26 80% 64% 81% Yes 59 87% 75% 87% No % 76% 92% Yes % 79% 93% <0.01 <0.05 No 27 67% 59% 77% P= <0.01 <0.05

28 Variable Age at RT Age at first surgery Gender Grade Recurrent prior to RT Race Chemotherapy prior to RT GTR/NTR at time of radiation 3 Year Disease Control Estimates on Univariate Analysis N Local Control (%) P= Progression- Free Survival (%) P= Overall Survival (%) % 77% 91% > % 74% 90% % > % 78% 72% 90% 91% Female 76 92% 87% 99% <0.05 Male % 67% 84% % 81% 90% % 73% 91% Yes 18 93% 84% 100% No % 75% 89% White/Asian % 78% 92% Black/Hispanic 26 80% 64% 81% Yes 59 87% 75% 87% No % 76% 92% Yes % 79% 93% <0.01 <0.05 No 27 67% 59% 77% P= <0.01 <0.05

29 Variable Age at RT Age at first surgery Gender Grade Recurrent prior to RT Race Chemotherapy prior to RT GTR/NTR at time of radiation 3 Year Disease Control Estimates on Univariate Analysis N Local Control (%) P= Progression- Free Survival (%) P= Overall Survival (%) % 77% 91% > % 74% 90% % > % 78% 72% 90% 91% Female 76 92% 87% 99% <0.05 Male % 67% 84% % 81% 90% % 73% 91% Yes 18 93% 84% 100% No % 75% 89% White/Asian % 78% 92% Black/Hispanic 26 80% 64% 81% Yes 59 87% 75% 87% No % 76% 92% Yes % 79% 93% <0.01 <0.05 No 27 67% 59% 77% P= <0.01 <0.05

30 Variable 3 Year Disease Control Estimates on Univariate Analysis N Local Control (%) P= Progression- Free Survival (%) P= Overall Survival (%) P= Location Posterior fossa % 72.0% 86.5% Supratentorial % 83.4% 98.2% Duration between last surgery and start of RT* 56 days 63 84% >56 days 57 85% 73% 95% 79% 90% Total Dose Total Dose in patients who had GTR/NTR Total Dose in patients who had STR 54 Gy 70 89% 78% 94% >55.8 Gy % 74% 88% 54 Gy 60 91% 80% 97% >55.8 Gy 92 87% 77% 90% 54 Gy 10 76% 65% 76% >55.8 Gy 17 61% 56% 78% * Non-chemo patients

31 Variable 3 Year Disease Control Estimates on Univariate Analysis N Local Control (%) P= Progression- Free Survival (%) P= Overall Survival (%) P= Location Posterior fossa % 72.0% 86.5% Supratentorial % 83.4% 98.2% Duration between last surgery and start of RT* 56 days 63 84% >56 days 57 85% 73% 95% 79% 90% Total Dose Total Dose in patients who had GTR/NTR Total Dose in patients who had STR 54 Gy 70 89% 78% 94% >55.8 Gy % 74% 88% 54 Gy 60 91% 80% 97% >55.8 Gy 92 87% 77% 90% 54 Gy 10 76% 65% 76% >55.8 Gy 17 61% 56% 78% * Non-chemo patients

32 Variable 3 Year Disease Control Estimates on Univariate Analysis N Local Control (%) P= Progression- Free Survival (%) P= Overall Survival (%) P= Location Posterior fossa % 72.0% 86.5% Supratentorial % 83.4% 98.2% Duration between last surgery and start of RT* 56 days 63 84% >56 days 57 85% 73% 95% 79% 90% Total Dose Total Dose in patients who had GTR/NTR Total Dose in patients who had STR 54 Gy 70 89% 78% 94% >55.8 Gy % 74% 88% 54 Gy 60 91% 80% 97% >55.8 Gy 92 87% 77% 90% 54 Gy 10 76% 65% 76% >55.8 Gy 17 61% 56% 78% * Non-chemo patients

33 Variable Location Duration between last surgery and start of RT* Total Dose Total Dose in patients who had GTR/NTR Total Dose in patients who had STR 3 Year Disease Control Estimates on Univariate Analysis Local Progression- Overall N Control P= Free Survival P= Survival (%) (%) (%) Posterior fossa % 72.0% 86.5% Supratentorial % 83.4% 98.2% 56 days 63 84% >56 days 57 85% 73% 95% 79% 90% 54 Gy 70 89% 78% 94% >55.8 Gy % 74% 88% 54 Gy 60 91% 80% 97% >55.8 Gy 92 87% 77% 90% 54 Gy 10 76% 65% 76% >55.8 Gy 17 61% 56% 78% P= On multivariate analysis, extent of resection maintained significance for improved local control and disease free survival, with borderline association with overall survival (p = 0.057) female gender maintained significance for better overall survival

34 SJYC07 Multi-institutional trial using riskadapted therapy to treat children <3 years old with malignant brain tumors including ependymoma Sought, for the first time, a prospective validation of retrospective data on the impact of molecular subgroup on outcomes in ependymoma ASCO 2018, Upadhyaya et al

35 Schema Maximum safe surgical resection Induction chemotherapy MTX/VCR/CTX/cisplatin Residual disease + second-look surgery 54 Gy radiation (CTV = 5 mm) 6 cycles of oral maintenance chemotherapy with cyclophosphamide, topotecan alternating with erlotibib

36 Patients Between 2008 and 2016, 54 children with ependymoma (median age, 1.6 years; range, ) All M0 based on imaging DNA methylation-based tumor subgroups: PF-A: 42 (78%) ST-RELA: 8 (15%) ST-YAP: 4 (7%) Similar patient age, tumor grade, and extent of resection across subgroups Median follow-up: 3.6 years

37 PFS and OS of Entire Cohort PFS by Subgroups 91% OS at 4 years Recurrence was distant (n = 7), local (n = 6), or combined (n = 1) p = 0.4 PFS by Extent of Resection PFS for PF-A with and without 1q gain p < 0.05 p = 0.15

38 Lesson #4 In craniopharyngioma, proton therapy with limited CTV margins reduces the radiation dose to developing neural tissue without compromising disease control Proton plan IMRT plan

39 University of Florida Craniopharyngioma Treatment Guidelines GTV = Gross disease

40 University of Florida Craniopharyngioma Treatment Guidelines GTV = Gross disease CTV = GTV + 5 mm, encompassing ventricle surfaces in contact with cyst

41 University of Florida Craniopharyngioma Treatment Guidelines GTV = Gross disease CTV = GTV + 5 mm, encompassing ventricle surfaces in contact with cyst PTV = CTV + 3 mm

42 University of Florida Craniopharyngioma Treatment Guidelines Prescription Dose PTV = 54 Gy

43

44 RT2CR Phase II trial for children with craniopharyngioma treated with proton therapy using 5 mm CTV Comparison cohort Phase II trial of conformal or intensity-modulated photon therapy using 5 mm CTV margin Trial Modality Patients Dose CTV Margin RT2CR Proton Gy 5 mm RT1 Photon Gy 5 mm PI: T. Merchant

45 RT2CR Treatment at the University of Florida Follow-up testing at St. Jude Imaging Time Points Year 1 every 3 months Year 2 every 6 months Year 3 every 6 months Year 4 every 6 months Year 5 every 6 months Evaluations/Schedule Protocol-based Assessments Months after RT Start Imaging Diagnostic MR X X X X X X X X X X X X X Investigational MR X X X X PET-FDG X X X PET-methionine X X X Clinical-Standard Assessment/Triage X X X X X X X X X X X X X Lab: CBC X X X X X X X X X X X X X Lab: Chemistry X X X X X X X X X X X X X Lab: Endocrine Screen X X X X X X X X X X X X X Audiometry X X X X X X Endocrine Clinic X X X X X X Neurology Clinic X X X Ophthalmology X X X X X X Physical Exam X X X X X X X X X X X X X Clinical-Investigational Endocrine/Provocative X X X Sleep/Fatigue Research Questionnaires X X X X X X X X X X X X X Actigraphy X X X X X X Melatonin/Core Temp X X X X X X Function Laboratory X X X X X X X Sleep Evaluation X X X Psychology X X X X X X Questionnaires/QOL X X X X X X Laboratory- Investigational Genomics X X Cytokines X X X X X X X

46 Merchant et al, ASTRO 2017 Comparative Results Progression-Free Survival Probability Months Since Initiation of Irradiation RT1 RT2CR Proton cohort median follow-up 36.5 months (range months)

47 Merchant et al, ASTRO 2017 Comparative Results Overall Survival Probability Months Since Initiation of Irradiation RT1 RT2CR

48 Merchant et al, SIOP 2017 Academic Achievement Scores: Proton vs Photon Reading Scores Math Scores Baseline 36 months 92 Baseline 36 months Proton Photon Proton Photon p= p=0.0263

49 Conclusions Progression-free survival estimates for proton therapy were comparable to those reported for children treated using photons Cognitive testing results from two prospective trials comparing proton and photon cohorts showed preservation of academic achievement for those treated with proton therapy compared to conformal radiation therapy using photons Final analysis will be performed 3 years after the last patient has been treated (early 2019)

50 Lesson #5 Treatment technique and risk factors impact craniopharyngioma tumor control these are applicable beyond particle therapy

51 University of Florida Craniopharyngioma Treatment Guidelines GTV = Gross disease CTV1 = GTV + 5 mm, encompassing ventricle surfaces in contact with cyst PTV1 = CTV1 + 3 mm CTV2 = GTV

52 University of Florida Craniopharyngioma Treatment Guidelines GTV = Gross disease CTV1 = GTV + 5 mm, encompassing ventricle surfaces in contact with cyst PTV1 = CTV1 + 3 mm CTV2 = GTV PTV1 = CTV2 + 3 mm

53 University of Florida Craniopharyngioma Treatment Guidelines Prescription Dose PTV1 = 45 Gy PTV2 = 54 Gy

54 Active Cyst Monitoring Week 2: GTV (red) Week 3: Cyst drained via ommaya Week 4: Cyst reaccumulating Week 5: Cyst needs repeat drainage Of the 94 children on RT2CR, we observed cyst expansion required replanning (n=8), drainage (n=4), or both (n=2)

55 Additional Research

56 Lesson #6 Proton therapy is not associated with unexpected toxicity ependymoma and craniopharyngioma

57 Brainstem Tolerance in Pediatric Radiotherapy

58 Murmurs Among the Zealots

59 Fooled by Randomness? No matter how sophisticated the person, abstract statistical information does not sway us as much as the anecdote. - Nassim Talib

60 Symptomatic brainstem toxicity in ependymoma patients Photon series Rate % Merchant (Lancet 2009) 3/ % Sato (Cancer 2017) 3/38 7.9% Nanda (IJROBP 2017) 5/ % Total 11/ %

61 Symptomatic brainstem toxicity in ependymoma patients Photon series Rate % Merchant (Lancet 2009) 3/ % Sato (Cancer 2017) 3/38 7.9% Nanda (IJROBP 2017) 5/ % Total 11/ % Proton series MacDonald (Neurooncology 2013) Ares (Journal of Neurooncology 2016) 0/70 0 1/50 2% Sato (Cancer 2017) 3/41 7.3% Indelicato (Acta Oncologica 2017) 10/ % Total 14/ %

62 Limitations to current literature 1. Era bias related to imaging technology - Progression vs toxicity 2. Inconsistent toxicity classification and grading - CTCAE is ambiguous and non-specific 3. Existing data sets are disease-specific and include non-relevant patients - Ex: supratentorial ependymomas, S-PNETs 4. Studies report nominal prescribed dose, not brainstem dose 5. Inconsistent/crude definition of brainstem OAR 6. Rare events preclude robust multivariate analyses

63 Potential Risk Factors for Pediatric Patients Dose to brainstem Gender Tumor size Co-morbidity Extent of resection Surgical toxicity Systemic therapy Age Race Target volume Hydrocephalus Number of operations CSF shunting Interval to radiation

64

65 Brainstem necrosis was defined by new or progressive symptoms following radiation involving motor weakness or cranial nerve V-VII or IX-XII corresponding radiographic abnormality within the brainstem in the absence of local disease progression Inclusion criteria: Patients 21 years old with a posterior fossa tumor Exclusion criteria: Intrinsic brainstem tumors (eg. brainstem glioma) Prior radiation to the brain or skull base Photon therapy component >5% Non-standard fractionation (not 1.8 Gy/fx) Less than 6 weeks of followup from the completion of radiation Absence of follow-up MRI

66 Grading Scale Global Characterization Brainstem Symptoms Cranial Nerve Deficits Grade 2 Grade 3 Grade 4 Grade 5 Life-threatening; inability to perform basic age-appropriate self-care functions Minor; interferes to some extent with patient's usual functioning Minor loss of strength Minor deficit Major; incapacitating, significantly interferes with patient's usual functioning Major loss of strength requiring functional aid Moderate deficit Complete paralysis, respiratory failure Complete loss of function in multiple cranial nerves Intervention HBO; steroids Multiagent Prolonged inpatient management of vital function Death

67 Reported Proton Outcomes Median f/u Total Patients With Necrosis Overall Rate %

68 Reported Proton Outcomes Median f/u Total Patients With Necrosis Overall Rate Grade % 1.3%

69 Reported Proton Outcomes Median f/u Total Patients With Necrosis Overall Rate Grade 3+ Grade % 1.3% 0.4%

70 Reported Photon Outcomes Total Patients With Necrosis Overall Rate Grade 3+ Grade % 1.3% 0.4% % 3.3% 1.7%

71 Dose Specifics With brainstem necrosis Without brainstem necrosis Prescription Dose (Gy) Brainstem (Gy) D50% D10% Max (0.1 cc) Proton Photon Proton Photon

72 Dose Specifics With brainstem necrosis Without brainstem necrosis Brainstem (Gy) Prescription Dose (Gy) D50% D10% Max (0.1 cc)

73 119 pediatric patients with non-metastatic posterior fossa ependymoma treated between June February 2017 University of Florida Ependymoma Treatment Guidelines CTV1 CTV1 Dose CTV2 CTV2 Dose GTV + 5 mm 54 Gy GTV 59.4 Gy* * If 3 y/o with a GTR/NTR, no CTV2 boost In cohort of 119 subjects, Median radiation dose in children 3 years old: 54 Gy 93% of children over 3 years old received 59.4 Gy

74 Goal Dose: D50% 61 Gy D10% 63 Gy D90% 44 Gy University of Florida Brainstem Dose Constraints Before October 1, 2013 Per Children s Oncology Group AC0831 Max Dose: D50% 62 Gy D10% 64 Gy D90% 59 Gy

75 Goal Dose: D50% <52.4 Gy D10% <55.4 Gy 0.1cc Max <56.6 Gy University of Florida Brainstem Dose Constraints After October 1, 2013 Per Indelicato et al, 2014 No plan should exceed any Max Dose metric No plan should exceed more than 1 Goal Dose metric Max Dose: D50% <54 Gy D10% <56 Gy 0.1cc Max <58 Gy Exception: Plans for kids <5 y/o should not exceed any Goal Dose metric Brainstem (Gy) With brainstem necrosis Without brainstem necrosis D50% D10% Max (0.1 cc)

76 Freedom from grade 2+ necrosis (%) Median follow-up: 3.1 years overall 4.4 years in 63 patients treated before October 1, years in 56 patients treated after October 1, 2013 Treated prior to October 1, 2013 (1.5 yr: 87%) Treated after October 1, 2013 (1.5 yr: 100%) * Significantly more patients in the pre-2013 cohort received chemotherapy before radiation Years

77 University of Florida Brainstem Dose Constraints After October 1, 2013 Goal Dose: D50% <52.4 Gy D10% <55.4 Gy 0.1cc Max <56.6 Gy Max Dose: D50% <54 Gy D10% <56 Gy 0.1cc Max <58 Gy No plan should exceed any Max Dose metric No plan should exceed more than 1 Goal Dose metric Exception: Plans for kids <5 y/o should not exceed any Goal Dose metric

78 100 Local control (%) Treated prior to October 1, 2013 (1.5 yr: 93.6%) Treated after October 1, 2013 (1.5 yr: 92.4%) p= Years

79 Conclusions Modern radiotherapy techniques result in a 0-10% risk of brainstem toxicity Need more data on interplay of dose and clinical factors UF Brainstem Guidelines offer a starting point for double-scattered proton therapy and IMRT

80 Vasculopathy Following Cranial Radiation

81 2007 Reviewed 345 survivors of cranial radiation Median f/u 54 months Risk factors for moyamoya: Dose to the optic chiasm NF-1 Younger age Optic pathway tumors

82 2017 2,202 French survivors of childhood cancer (treated ) Dosimetry to Circle of Willis estimated using phantom reconstruction in scalable phantoms Median f/u: 26 years 54 pts found to have a stroke (72% ischemic) Risk factors for stroke: 1. Increased dose to the Circle of Willis 2. Male gender (for ischemic stroke)

83 El-Fayech et al, 2017

84 15 July 2018 Objectives: To estimate the rate of vasculopathy following proton therapy in pediatric patients with C/Skull Base tumors To identify risk factors for developing vasculopathy

85 Methods pediatric patients treated with proton therapy for C/skull base tumors at UF All enrolled on prospective outcomes tracking study Recommend imaging: MRI q3-4 months for 3 years, q6 months for 5 years, then annually MRA every 1-2 years for sellar/suprasellar, brainstem, and skull base tumors

86 Methods Endpoints: Vasculopathy Any asymptomatic vessel narrowing identified by imaging, transient ischemic attacks (TIAs), and cerebrovascular accidents (CVAs) Serious Vasculopathy Events resulting in permanent neurological complications or requiring revascularization surgery

87 Methods Multivariate logistic regression used to identify factors associated with toxicity Variables Age, NF, extent of surgical resection, history of postoperative stroke, chemotherapy, total prescribed dose, and dose to the optic chiasm, optic nerves, and hypothalamus Median follow-up: 3.0 years ( )

88 Patient Characteristics Median Age [Range] 7.6 years [ ] Median Prescribed Dose [Range] 54 Gy RBE [ ] Sex Male 357 (55%) Female 294 (45%) Histology Craniopharyngioma 140 (22%) Ependymoma 135 (21%) Low-grade glioma 132 (20%) Medulloblastoma/PNET 80 (12%) Ewing/RMS/NRSTS 74 (11%) Other 90 (14%) Extent of Surgical Resection GTR/NTR 251 (39%) STR/Biopsy 370 (57%) None 30 (4%) Tumor Location Sellar/Suprasellar 276 (42%) Thalamic/Basal Ganglia 70 (11%) Hemispheric/Lateral Venticles 127 (20%) Posterior Fossa 178 (27%)

89 100 Freedom from event (%) year risk of any vasculopathy = 6.4% 3 year risk of serious vasculopathy = 2.6% Years

90 Results Multivariate Analysis Asymptomatic Events Thirty patients developed asymptomatic vessel narrowing on imaging during the study period Serious Events Seven patients (1.2%) developed CVA with permanent neurological deficits (CTCAE Grade 4 toxicity) Four patients had revascularization surgery Any Vasculopathy Factor 3-yr Rate Age <5 y.o. Dmax Optic Chiasm ( 54 CGE) 8.4% vs. 5.4% (p<0.01) 13.1% vs. 2.2% (p<0.001)

91 Results Multivariate Analysis Asymptomatic Events Thirty patients developed asymptomatic vessel narrowing on imaging during the study period Serious Events Seven patients (1.2%) developed CVA with permanent neurological deficits (CTCAE Grade 4 toxicity) Four patients had revascularization surgery Any Vasculopathy Serious Vasculopathy Factor 3-yr Rate 3-yr Rate Age <5 y.o. 8.4% vs. 5.4% (p<0.01) Dmax Optic Chiasm ( 54 CGE) 13.1% vs. 2.2% (p<0.001) 3.8% vs. 1.7% (p<0.05) Gender, tumor histology, tumor location, chemotherapy, extent of surgery, and co-morbidities were not associated with increased risk

92 Conclusions Childhood cancer survivors are at high risk for radiation-related vasculopathy Young children and those receiving 54 Gy to the optic chiasm were at highest risk Incidence of serious vasculopathy following proton therapy similar to historical photon data

93 Comparative Toxicity on RT2CR Trial Modality Patients Dose CTV Margin RT2CR Proton Gy 5 mm RT1 Photon Gy 5 mm Median age of craniopharyngioma patients Photon cohort: 9 years Proton cohort: 9.4 years Severe complications after irradiation were defined as: brain or brainstem necrosis clinically significant vasculopathy resulting in permanent neurological complications or requiring revascularization surgery permanent neurological deficits not related to necrosis or vasculopathy

94 Comparative Toxicity on RT2CR The cumulative incidence of severe complications were similar to those observed in patients treated using photon therapy Merchant et al, ASTRO 2016

95 Lesson #7: Recommendations for limiting toxicity Regardless of radiation modality, If goal is to keep brainstem toxicity <5%, apply UF brainstem dosimetric guidelines based on age and extent of resection If estimated dose the Circle of Willis is >10 Gy, obtain baseline MRA and integrate with followup imaging * * This position does not encompass pencil beam proton therapy

96 Thank you Acknowledgements Tom Merchant Santosh Upadhyaya Julie Bradley Ronny Rotondo Matt Hall