Chika Nwachukwu, Ph.D. MS IV Radiation Oncology Rotation

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1 Chika Nwachukwu, Ph.D. MS IV Radiation Oncology Rotation

2 Background Histology/Tumor Characteristics Presenting Symptoms/diagnosis Treatment/outcome Patient cohort Research on HRQOL

3 Slow growing indolent 10-15% of all glioma 30-50% of CNS tumors in children Can occur anywhere in the CNS Multiple different histologies Pilocytic Astrocytoma Diffuse Fibrillary Astrocytoma * Excellent overall survival

Histology WHO grade Location Age Pilocytic Astrocytoma I Any where (Cerebellum, optic pathway,

Astrocytoma Pleomorphic Xanthroastrocyto ma II Supratentorial, deep midline, cervico -

Supratentorial (temporal) 5-19 yrs Ganglioglioma II Temporal lobes 9.

4 Histology WHO grade Location Age Pilocytic Astrocytoma I Any where (Cerebellum, optic pathway, dorsal exophytic brain stem 5-9yrs (peak) Diffuse fibrillary astrocytoma Pilomyxiod Astrocytoma Pleomorphic Xanthroastrocyto ma II Supratentorial, deep midline, cervico - medullary 30 yrs (peak) 10% <20 yrs of age II Hypothalamic region <18months (mean) II Supratentorial (temporal) 5-19 yrs Ganglioglioma II Temporal lobes 9.5yrs (mean) *Subepndymal giant cell astrocytoma I Oligodendrioma II Frontal lobe <14yrs Children with TSS Sievert A et al J Neurooncology 95:

5 Generalizing ICP Morning headaches Nausea Vomiting Lethargy Signs Upward gaze CNVI palsies papilledema Localizing Focal neurological findings Seizures Endocrinopathies

6 Surgery (Gross Total Resection) Cerebellum and Superficial Cerebrum tumors Most consistent prognostic factor (PFS, OS) Surgery (subtotal resection) Repeat surgery for residual tumor Wait and see (MRI 3-6months): 45-65% 5yrs PFS RT: (increase PFS but not OS) Biopsy only or no surgical approach feasible (anatomic constraints) Adjuvant therapy RT (45-54Gy): Conflicting retrospective data Chemo: Carboplatin/VCR vs. Thioguanine/procarbazine, CCNU/vincristine(TCPV) Target-therapies: RAS pathway (lonarfanib) and mtor (everolimus) Kortmann RD et al 2003 Strahlenther Onkol

8 PFS OS 10 and 20 year PFS= 60% and 50% respectively 10 and 20 year OS= 90% and 80% respectively Youland R et al 2013 J pediatr hematol Oncol

9 PFS OS Youland R et al 2013 J pediatr hematol Oncol

10 In medical oncology literature since 1990 Relatively recent in brain tumor patients Important outcome measure in clinical trials Self-reported validated questionnaires Physical, psychological, emotional, and social issues European organization for Research and Cancer treatment (EORTC)-QLQ-C30 EORTC BN-20 (brain cancer)

The items are scaled, scored and transformed to linear scale ranging from 0-100 A high scale score represents a higher response level.

12 The items are scaled, scored and transformed to linear scale ranging from A high scale score represents a higher response level. A high score for the global health status / QoL represents a high QoL, Thus a high score for a functional scale represents a high / healthy level of functioning, but a high score for a symptom scale / item represents a high level of symptomatology / problems. Difference > 10 are classified as clinically meaningful and changes > 20 points are classified as large effects Taphoorn M et al 2010 Neuro Oncology

13 351 patients (path proven LGG) 314(alive) 37(dead) 314 patients (3yr f/u & -> 18yrs age 137 (respondents) patients 121 (participants) 16 (declined)

14 Non-Participants Participants P-value Baseline Characteristics No. of patients (%) No. of patients (%) n=230 n=121 Age at Diagnosis, (yrs) Mean Median Range Age at Survey completion, (yrs) Mean Median Range Follow-up, (yrs) Mean Median Range Gender Female 95(41.3) 64 (53) * Male 135(58.7) 57 (47) Seizures Yes 93(40) 45(37) No 135(59) 76(63) Not sure 2(1) 0(0) Headaches Yes 108(47) 67(55) No 120(52) 54(45) Not sure 2(1) 0(0) Motor Weakness Yes 55(24) 35(29) No 173(75) 86(71) Not sure 2(1) 0(0) Sensory Symptoms Yes 60(26) 27(22) No 168(73) 94(78) Not sure 2(1) 0(0) Participants are very similar to non-participants except in gender, extent resection, and recurrence

15 Baseline Characteristics Non-Participants Participants P-value No. of patients (%) No. of patients (%) n=230 n=121 Histology Glioma 104 (45) 51(42) Pilocytic Astrocytoma 106(46) 62 (51) Subependymal Giant Cell Astrocytoma/other 20(9) 8 (7) Grade I 133(57) 77(64) II 97(42) 44(36) Primary Site Brain Stem 7(3) 2 (2) Cerebellum 52(23) 41 (34) Cortical 86(37) 46 (38) Deep Structure 66(29) 22 (18) Multiple 17(7) 10 (8) Spinal Cord 2(1) 0(0) Laterality Bilateral/ Midline/ other 61(27) 29 (24) Left 78(34) 44 (36) Right 91(39) 48 (40) Extent of Resection Biopsy (BX) 32(14) 5 (4) *0.005 Gross Total resection (GTR) 143(62) 93 (77) Subtotal (STR) 55(24) 23 (19) Post-operative Treatment Observation 164(71) 97 (80) Radiotherapy 55(24) 21 (17) Radiotherapy +Chemotherapy 5(2) 2 (2) Chemotherapy 6(3) 1(1) Radiation Treatment-only Yes 55(24) 21(17) No 175(76) 100(83) Recurrence Yes 66(29) 30(25) * No 146(63) 91(75) Not sure 18(8) 0(0) Survival PFS Survival Overall Survival

16 Patients n=121 EORTC QLQ C30 baseline domains (Sd) Global Scores 78 (18.1) Functional Physical 91.9 (21.1) Role 91.3 (22.7) Emotional 79.9 (22.5) Cognitive 83.5 (20.9) Social 87.3 (24.7) Symptoms Fatigue 16.9 (20.4) Nausea/Vomiting 2.4 (6.6) Derogar M 2012 Reference values (All Adults Swedish) n= (22.8) 88.0 (18.3) 88.2 (23.9) 85.8 (18.7) 88.1 (16.9) 91.2 (19.0) 19.1 (21.7) 2.6 (9.3) Pediatric LGG patients have similar QOL to healthy adults, except appetite loss and financial burden Pain 10.2 (20.5) Dyspnea 6.6 (16.5) Insomnia 15.4 (22.8) Appetite Loss 18.1 (1.7) Consiptaion 7.5 (20.0 Diarrhea 7.3 (18.5) Financial 16.2 (29.4) 18.9 (25.7) 16.3 (24.3) 17.5 (25.9) 3.3 (12.8) 5.4 (6.1) 5.6 (15.9) 4.4 (16.2) Derogar M 2012 Acto Oncologica 51:10-16, Scott N 2008 EORTC manual, Gufstasson M 2006 Support Care Cancer 14: , Zareifar S2012 Indian J Pediatr 17:177-1

17 n=121 EORTC QLQ C30 baseline domains (Sd) Global Scores 78 (18.1) Functional Derogar M 2012 Reference values LLG adults (All Adults Swedish) n=39 n= (22.8) Gustafsson M (21.0) Physical 91.9 (21.1) 88.0 (18.3) 82.6 (27.6) Role 91.3 (22.7) Emotional 79.9 (22.5) Cognitive 83.5 (20.9) Social 87.3 (24.7) Symptoms 88.2 (23.9) 85.8 (18.7) 88.1 (16.9) 91.2 (19.0) 71.1 (32.1) 73.4 (20.5) 71.2 (23.5) 77.5 (33.0) Adult LGG patients have lower cognitive and social functioning as well as more symptoms Fatigue 16.9 (20.4) 19.1 (21.7) 29.5 (26.3) Nausea/Vomiting 2.4 (6.6) 2.6 (9.3) 2.2 (6.9) Pain 10.2 (20.5) Dyspnea 6.6 (16.5) 18.9 (25.7) 16.3 (24.3) 21.9 (27.7) 21.9 (29.3) Insomnia 15.4 (22.8) Appetite Loss 18.1 (1.7) Consiptaion 7.5 (20.0 Diarrhea 7.3 (18.5) 17.5 (25.9) 3.3 (12.8) 5.4 (6.1) 5.6 (15.9) 26.3 (29.2) 7.0 (17.6) 8.8 (18.5) 4.4 (13.8) Financial 16.2 (29.4) 4.4 (16.2) 15.3 (27.9) Derogar M 2012 Acto Oncologica 51:10-16, Scott N 2008 EORTC manual, Gufstasson M 2006 Support Care Cancer 14: , Zareifar S2012 Indian J Pediatr 17:177-1

18 n=121 EORTC QLQ C30 baseline domains (Sd) Global Scores 78 (18.1) Functional Derogar M 2012 Reference values LLG adults (All Adults Swedish) n=39 n= (22.8) Gustafsson M (21.0) Zareifar s 2011 AML/ALL children total n= (19.43) Physical 91.9 (21.1) 88.0 (18.3) 82.6 (27.6) (19.53) Role 91.3 (22.7) Emotional 79.9 (22.5) Cognitive 83.5 (20.9) Social 87.3 (24.7) Symptoms Fatigue 16.9 (20.4) 88.2 (23.9) 85.8 (18.7) 88.1 (16.9) 91.2 (19.0) 19.1 (21.7) 71.1 (32.1) 73.4 (20.5) 71.2 (23.5) 77.5 (33.0) 29.5 (26.3) (18.4) 76 (20.66) (17.78) 84 (18.62) (18.62) Children undergoing treatment for AML/ALL have more nausea and vomiting Nausea/Vomiting 2.4 (6.6) 2.6 (9.3) 2.2 (6.9) 12.5 (20.56) Pain 10.2 (20.5) Dyspnea 6.6 (16.5) 18.9 (25.7) 16.3 (24.3) 21.9 (27.7) 21.9 (29.3) (16.13) 4.33 (14.72) Insomnia 15.4 (22.8) Appetite Loss 18.1 (1.7) Consiptaion 7.5 (20.0 Diarrhea 7.3 (18.5) 17.5 (25.9) 3.3 (12.8) 5.4 (6.1) 5.6 (15.9) 26.3 (29.2) 7.0 (17.6) 8.8 (18.5) 4.4 (13.8) (23.99) 21 (23.04) 2 (7.95) 5.33 (12.28) Financial 16.2 (29.4) 4.4 (16.2) 15.3 (27.9) (33.62) Derogar M 2012 Acto Oncologica 51:10-16, Scott N 2008 EORTC manual, Gufstasson M 2006 Support Care Cancer 14: , Zareifar S2012 Indian J Pediatr 17:177-1

19 QLQ-BN20 Baseline (SD) Overall 11.8 (14.2) Future Uncertainty 0.13 (0.17) Visual Disorders 8.7 (18.2) Motor Dysfunction 15.4 (24.6) Communication Difficulty 14.5 (23.4) Headaches 16.5 (21.6) Seizures 4.8 (15.9) Drowsiness 20.2 (24.6) Itchy Skin 7.8 (19.2) Hair Loss 8.4 (20.5) Weak Legs 7.8 (22.8) Bladder Control 9.3 (25.4) Budrukkar A 2009 Low grade glioma (n = 71) 17.9 (21.2) 17.6 (18.3) 25.7 (21.6) 28.9 (25.2) 21.6 (22.6) 27.1 (29.9) 12.3 (22.2) 2.9 (9.4) 15.5 ( 25.1) Motor SXS: more problems with role functioning and motor dysfunction Budrukkar A 2009 J neurooncology

20 Motor SXS No Yes QLQ-C30 Mean Mean p-value Global Functional Physical Role * Emotional Cognitive Social Symptoms Fatigue Nausea/Vomiting Pain Dyspnea Insomnia Appetite Loss Constipation Diarrhea Financial Motor SXS No Yes QLQ-BN20 Mean Mean P-value Overall Future Uncertainty Visual Disorders Motor Dysfunction * Communication Difficulty Headaches Seizures Drowsiness Itchy Skin Hair Loss Weak Legs Bladder Control Motor SXS: more problems with role functioning and motor dysfunction

21 Bilateral/Midline/ Other Left Right QLQ-C30 Mean Mean Mean p-value Global Functional Physical Role Emotional Cognitive Social Symptoms Fatigue * Nausea/Vomiti ng Pain Dyspnea Insomnia Appetite Loss Constipation Diarrhea Financial Bilateral or midline tumors :more complaints of fatigue. (No Brain specific differences)

22 Cerebellu m Deep Structures Location Brainstem Cortical Multiple QLQ-C30 Mean Mean Mean Mean Mean p-value Global Functional Physical Role Emotional Cognitive * Social Symptoms Fatigue * Nausea/V omiting Pain * Dyspnea Insomnia Appetite Loss Constipati on Diarrhea Financial Cerebellu m Deep Structures Brainstem Cortical Multiple QLQ-BN20 Mean Mean Mean Mean Mean P-value Overall * Future Uncertaint y Visual Disorders Motor Dysfuncti on ) Deep tumors more cognitive complaints than cerebellum or cortical 2.) Brain stem tumors and Deep tumors more complaints of fatigue than cortical tumors 3.) Brain stem tumors more pain in comparison to cortical tumors 4.) Brain stem tumors more motor dysfunction compared to all other tumor types 5.) Deep tumors more bladder control complaints in comparison to cortical tumors * Communi cation Difficulty Headache s Seizures Drowsines s Itchy Skin Hair Loss Weak Legs Bladder Control *

23 GTR STR/Bx QLQ-BN20 Mean Mean P-value Overall Future Uncertainty Visual Disorders Motor Dysfunction Communicati on Difficulty Headaches Seizures Drowsiness Itchy Skin Hair Loss Weak Legs Bladder Control * More bladder control with STR/Bx (No C30 specific differences)

24 Radiation Therapy No Yes QLQ-C30 Mean Mean p-value Global Functional Physical * Role * Emotional Cognitive Social Symptoms 9 16 Fatigue Nausea/Vomiting Pain Dyspnea Insomnia Appetite Loss Constipation * Diarrhea Financial Post-Op TX Obs RT RT+Chemo QLQ-C30 Mean Mean Mean p-value Global Functional Physical * Role * Emotional Cognitive Social Symptoms Fatigue Nausea/Vomiting Pain * Dyspnea Insomnia Appetite Loss Constipation * Diarrhea * Financial ) Worse physical and role functioning in patients with RT or RT+Chemo 2.) Addition of Chemo significantly diminishes PF and RF 3.) More Constipation in patients with RT 4.) More problems with diarrhea and pain in chemo+rt

25 Radiation Therapy No Yes QLQ-BN20 Mean Mean P-value Overall * Future Uncertainty Visual Disorders * Motor Dysfunction * Communication Difficulty Headaches Seizures Drowsiness * Itchy Skin Hair Loss Weak Legs * Bladder Control 4 30 <.0001* Post-op TX Obs RT RT+Chemo QLQ-BN20 Mean Mean Mean P-value Overall * Future Uncertainty Visual Disorders * Motor Dysfunction * Communication Difficulty Headaches Seizures Drowsiness Itchy Skin Hair Loss Weak Legs * Bladder Control <.0001* 1.) More complaints of visual disturbances, motor dysfunction, weak legs, bladder control in patients receive RT or RT+chemo 2.) Addition of Chemo significantly worsens weak legs and bladder control

26 Recurrence No Yes QLQ-C30 Mean Mean p-value Global Functional Physical * Role * Emotional Cognitive Social * Symptoms Fatigue Nausea/Vomiti ng Pain Dyspnea Insomnia Appetite Loss Constipation Diarrhea Financial * Recurrence No Yes QLQ-BN20 Mean Mean P-value Overall Future Uncertainty Visual Disorders * Motor Dysfunction Communication Difficulty Headaches Seizures Drowsiness Itchy Skin Hair Loss Weak Legs * Bladder Control ) Worse role, physical and social functioning with recurrence 2.) Increased financial burden with recurrence 3.) more visual disorder and weak leg complaints with recurrence

27 CLQ- C30 Role CLQ- C30 Physical CLQ-C30 Independent variables Pain Standardized motor weakness _ * Standardized XRT Standardized Post Op tx * * * Final recurrence _ * Standardized location * Independent BN20 Motor BN20 Weak Legs variables Dysfunction BN20 Bladder Control Standardized location * Standardized motor weakness Standardized XRT * * * Standardized Post Op tx _ <.0001* * Final recurrence _ Standardized extent resection _

28 In general pediatric patients with LGG have a great prognosis with OS at 10> 90% Pediatric LGG have good quality of life in comparison to adult LGG as well as other pediatric tumors Factors that affect quality of life are post-op tx, location of the tumor, recurrence of the disease

29 Mayo Dr. Nadia Laack Dr. Ryan Youland Catherine Chorieso ASCO- conquer cancer foundation medical student rotation OHSU Dr. Carol Marquez Dr. Arthur Hung Dr. Charlotte Kubicky Dr. John Holland Dr. Charles Thomas All the resident especially twin speak. Katie Atkins

30 Taphoorn M et al 2012 Review on Quality of Life Issues in patients with primary brain tumors. Neuro-Oncology klein M et al 2002 Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet 360: Derogar M et al 2012 Reference values for the EORTC QLQ-C30 quality of life questionnaire in a random sample of the Swedish population, Acta Oncologica 51:10-16 Scott N et al 2008 EORTC qlq-c30 Reference Values Gustafsson M et al 2006 The relationship between function, quality of life and coping in patients with low-grade glioma. Support Care Cancer 14: Zareifar S et al 2012 Evaluation of health related quality of Life in 6-18 years old patients with Acute Leukemia during Chemotherapy. Indian J Pediatrics 79: Douw L et al 2009 Cognitive and radiological effects of radiotherapy in patients with lowgrade glioma: long term follow-up. Lancet oncology 8: Budrukkar A 2009 Prospective assesment of quality of life in adult patients with primary brain tumors in routine neurooncology practice. J Neurooncology 95: Sievert A et al 2009 Pediatric Low-Grade glioma. J child Neurology 24: Shaw E et al 2003 Prospective clinical trials of intracranial low-grade glioma in adults and children. Neuro-oncology 5: Nageswara Rao AA 2012 Biologically targeted therapeutics in pediatric brain tumors 46: Youland R et al 2013 Prognostic factors and survival patterns in pediatric Low-grade gliomas over 4 decades Pediatric Hematol Oncol 35:

Radioterapia no Tratamento dos Gliomas de Baixo Grau

Radioterapia no Tratamento dos Gliomas de Baixo Grau Dr. Luis Souhami University Montreal - Canada Low Grade Gliomas Relatively rare Heterogeneous, slow growing tumors WHO Classification Grade I Pilocytic