Best of ASTRO Dr. Serra Kamer Ege Üniversitesi Tıp Fakültesi Radyasyon Onkolojisi

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1 Best of ASTRO 2017 Dr. Serra Kamer Ege Üniversitesi Tıp Fakültesi Radyasyon Onkolojisi

2 Hematoloji: 1. Allojenik TBI-Containing rejimlerde kranial boost un SSS hastalığına etkisi 2. Lenfoma tedavisine bağlı geç dönem yan etkilerin azaltılması 9 çalışma

3 Lenfoma tedavisine bağlı geç dönem yan etkilerin azaltılması 9 çalışma Volüm azaltılması: ISRT / INRT Doz azaltılması : 20 Gy in DLBCL in CMR Predictors of hypothyroidism İleri teknolojinin yeri (mediastinal RT için en iyi teknik) Butterfly-VMAT v full-arc VMAT ± DIBH Butterfly v Rainbow techniques IMRT photons v Protons ± DIBH Geç yan etki riskini azaltıcı yaklaşımlar: Life-style and cardiac disease risk Hasta seçimi RT for stage III-IV HL in CMR RT for Early stage ALCL

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5 Problem: Tanıda CNS tutulumlu ALL olgularında posttransplant CNS yineleme riski yüksek Hazırlama rejiminde Total body irradiation (TBI) occult rezidüel CNS hastalığı için yetersiz olabilir. TBI uygulamasına Kranial boost eklenmesinin etkinliği net olarak bilinmiyor.

6 Güncel Durum

7 Country Name Contact Austria Wolfgang Holter Australia Peter Shaw Belgium Sophie Dupont Brazil Vanderson Rocha Canada Tony Truong Czech Republic Petr Sedlacek Denmark Marianne Ifversen Finland Kim Vettenranta France Jean-Hugues Dalle Germany Peter Bader Hungary Gergely Krivan Israel Jerry Stein Italy Franco Locatelli Jordan Ayad Achmed Hussein Netherlands Marc Bierings New Zealand Lochie Teague via Peter Shaw Norway Anders Glomstein Jochen Büchner Saudi Arabia Ali Ahmari Slovakia Sabina Suffliarska Sweden Jacek Toporski Switzerland Tayfun Güngör Turkey Akif Yesilipek United Kingdom Rob Wynn

8 Overview: Irradiation plan (TBI and Cranial irradiation) Age at time of conditioning CNS-Involvement Previous irradiation (Cranium) in Gy Irradiation-free interval TBI in Gy CNS Boost before SCT in Gy Total dose Cranium 48 months or MMD SCT neg pos no no no no no no no no no no no no neg <24 months no no no no >48 months MSD or MD SCT or MMD BM 8/10 Active Pos: no months <24 months 24 months no no no no 6 no 6 6 no no

9 Amaç: Allojenik TX hastalarında TBI uygulamasına CB eklenmesinin postransplant CNS yinelemesi ile ilişkisinin değerlendirilmesi

10 Hasta Özellikleri Tek merkez-213 ALL patients received HSCT with TBI-based conditioning ( ) Male:Female = 3:2 Median yaş-tx = 17.9 yr (1.6 56) Median takip= 2.3 yr ( ) Remisyon durumu : CR1: 55.9%CR2: 33.3%CR3+: 8.9%

11 Hazırlama Rejimi Cyclophosphamide +/-Fludarabine TBI: 1.65 Gy BID x 8 fx to 13.2 Gy CB recommended if history CNS disease ve no previous cranial irradiation CB: Gy QD x 5 fx to 9-10 Gy Within 2 weeks before TBI All transplants allogeneic (UCB, MRD, URD) Conditioning Regimen

12 Hasta Özellikleri

13 CNS Yineleme 1.Leukemic blasts in CSF 2.Contrast-enhancing CNS lesion(s) on imaging attributed to leukemic involvement 3.Clinical symptoms consistent with CNS relapse

14 Yineleme Bölgesi(n:53) Bölge n Kemik iliği 34 CNS dışı extramedüller bölge 4 Kİ+CNS dışı extramedüller bölge 8 Total Non-CNS 46 CNS 3 CNS+Kİ 4 Total CNS 7

15 Grup CNS yineleme CNS-/CB- 4 (%2.5) CNS+/Prior CI 1 (%8.3) CNS+/CB- 2(%18.2) CNS+/CB+ 0 Total 7(%3) Grup n event risk p CNS+/CB- CNS+/CB- 2 yıllık CNS yineleme riski %0 %21(0-45) 0.03

16 OS ve DFS

17 Çalışmanın Zayıf Yönleri Retrospektif çalışma Event sayısı az; sadece 7 CNS yinelemesi CB seçimi hasta veya Klinisyen tercihi? Neurocognitive toksisite değerlendirmesi yok.

18 Sonuç: TX sonrası CNS yineleme riski boost ile azalır. Boost ileos veya DFS etkisi yok. Uzun dönem sağkalımda en önemli risk kemik iliği yinelemesi

20 Cardiac disease and lifestyle risk factors following Hodgkin lymphoma: An EORTC Lymphoma Group and GELA follow-up study Maja V. Maraldo, Francesco Giusti, Marleen A.E. van der Kaaij, Michel Henry-Amar, Berthe M.P. Aleman, John Raemaekers, Paul Meijnders, Elisabeth C. Moser, Hanneke C. Kluin-Nelemans, Michele Spina, Christophe Fermé, Catherine Fortpied & Lena Specht

21 Problem Hodgkin lenfoma (HL) hastalarında RT ve antrasiklin kullanımı ile ilişkili artmiş kardiak hastalık riski (CD) Buna karşın; CD riski ile ilişkili risk faktörleri de mevcut: Yüksek tansiyon Kolesterol yüksekliği Diyabet Obezite Sigara

22 Method: arası 9 EORTC-GELA randomized Çalışması trials (H1-H9) Takipte Kardiak olayların takibi da mail ile yollanan patientreported questionnaire (Life Situation Questionnaire, LSQ) Ischemic heart disease Congestive heart failure Arrhythmia Valvular disease Pericarditis Cardiac other

23 Sonuçlar: 1919 hasta cevabı 938 (49%) erkek Median yaş:29 Median takip: 14 yıl 416 hasta en az 1 event Clinical report forms: 6039 Life Situation Questionnaire (LSQ): 4735 patients eligible LSQ responders: 1919 patients Incomplete treatment information: 566 Dead: 1304 patients Non-participating centers: 739 patients LSQ non-responders: 2077 patients

24 Sonuçlar: Table III: Odds ratio vs. cardiac event Odds ratio 95% CI p-value High blood pressure at LSQ completion 2.7 (2.1,3.5) Elevated blood cholesterol levels at LSQ completion 2.6 (2.0,3.4) Diabetes at LSQ completion 3.5 (2.3,5.5) BMI at LSQ completion 1.3 (0.9,1.8) Smoking at LSQ completion 1.3 (0.9,1.7) LSQ Life Situation Questionnaire, CI confidence intervals.

25 Sonuç: For Hodgkin lymphoma patients The continued efforts to limit treatment exposure are important to minimize the risk of subsequent CD. Traditional lifestyle risk factors (such as high blood pressure, elevated blood cholesterol, and diabetes) are significantly associated to the risk of developing CD. Patient education, lifestyle intervention, and counseling should be encouraged at all treating institutions.

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27 Table I: Patient and treatment characteristics Patient characteristics, n (%) Gender Male 938 (48.9) Female 981 (51.1) Age at treatment start Years, median (range) 29 (10-69) Country The Netherlands 895 (46.6) France 722 (37.6) Belgium 150 (7.8) Italy 90 (4.7) Other 62 (3.2) Clinical stage I-II oranları? 1650 (86.0) III-IV 267 (13.9) Missisng 1 (0.01) BMI at baseline Wake-up call etkisi? BMI, median (range) 22 (12-49) Missing 129 (6.7) Smoking at baseline No 1181 (61.5) Yes 621 (32.4) Missing 117 (6.1) Family history of cardiac disease No 1541 (80.3) Yes 317 (16.5) Missing 61 (3.2) Length of follow-up Years, median (range) 14 (5-44) Treatment exposure, median (range) Mean heart dose [Gy] 21.5 (0-6.6) Anthracycline cumulative dose [mg/m 2 ] 161 (0-328 ) Vincristine cumulative dose [mg/m 2 ] 0 (0-25) Vinblastine cumulative dose [mg/m 2 ] 33 (0-441) Table II. Outcome at LSQ completion n (%) High blood pressure No 1467 (76.4) Yes 329 (17.1) Missing 123 (6.4) Elevated levels of blood cholesterol levels No 1273 (66.3) Yes 376 (19.6) Missing 270 (14.1) Diabetes mellitus No 1800 (93.8) Yes 96 (5.0) Missing 23 (1.2) BMI Underweight (<18.50) 52 (2.7) Normal range ( ) 974 (50.8) Overweight ( ) 644 (33.6) Obese (>=30.00) 221 (11.5) Missing 28 (1.5) Smoking No 1603 (83.5) Yes 289 (15.1) Missing 27 (1.4) İleri teknoloji, düşük kalp dozu ve hayat şekli önerileri ile risk LSQ Life Situation Questionnaire, BMI body mass index.

29 Consolidation Radiation Therapy for Advanced Hodgkin Lymphoma in Complete Metabolic Response by PET-CT or Gallium EJ Song, J Torok, Y Yu, J Chino, LR Prosnitz, AW Beaven, CR Kelsey Duke University Medical Center

30 Problem

31 Problem Randomize çalışma sonuçları tartışmalı- Tedavi klavuzu önerileri: Bulky disease PET+ disease after chemotherapy

32 Problem: Özgün RT yaklaşımı Düşük doz (~20 Gy) All sites of involvement Az hasta sayısı : 90 retrospective Tam Metabolik yanıtlı olgularda Chemo+RT ve Chemo etkinliğinin karşılaştırılması

33 Results 46 CMT (Median follow-up: 66 months) 4 Relapses (3 within RT field) 3 Salvage Chemo and ASCT + RT ABVD + RT 1 HL death 44 ChT alone (Median follow-up: 35 months) 7 Relapses (All at original sites; 6/7 non-bulky) 5 Salvage Chemo and ASCT + RT 2 Not eligible for transplant 4 HL deaths

34 Progression Free Survival Sonuçlar Progression-Free Survival Combined Modality Therapy CMT: 88% 95% CI [71-96%] ChT alone: 65% 95% CI [46-78%] p< Chemotherapy Alone Number at Risk Combined Modality Therapy Chemotherapy Alone Years

35 Overall Survival Sonuçlar Overall Survival Combined Modality Therapy Chemotherapy Alone CMT: 97% 95% CI [80-99%] ChT alone: 78% 95% CI [60-89%] p= Number at Risk Combined Modality Therapy Chemotherapy Alone Years

36 Multivariate Analysis

37 Öneriler Çalışma: 88% 5-y PFS with CMT, comparable to ebeacopp with less toxicity (?) UK LY-09: PFS & OS benefit from localized RT (Johnson JCO 2010) Another evidence that RT adds to ABVD But: in this study, 65% of ABVD alone did not need wide-field RT Any potential for future selection? Residual masses? ipet?

38 Role of Adjuvant Radiation Therapy for Early Stage Anaplastic Large Cell Lymphoma: Analysis of the NCDB Diana Julie, MD MPH

39 Problem ALCL tüm NHL % ~2-5 CD30+ 2 patolojik subtypes ALK+ % hastaların 60 genç erkek Aggressive klinik İyi prognoz (5-year OS 70-80%) ALK- yaşlı Daha az agresif klinik Kötü prognoz (5-year OS 30-40%) Sources: Liu 2017; Freedman 2017; Heidegger

40 Treatment Role of Adjuvant Radiation Therapy for Early Stage Anaplastic Large Cell Lymphoma 40

41 Sonuçlar Characteristic N (%) 2013, 7% 2004, 11% Age < (67) 2012, 10% (33) 2005, 10% Sex Male 570 (60) Female 377 (40) 2011, 8% Charlson-Deyo score (84) (12) 2 36 (4) 2010, 10% 2006, 10% Stage I 405 (43) II 542 (57) 2007, 10% B symptoms Absent 610 (64) Present 228 (24) 2009, 12% 2008, 12% Year of Diagnosis Role of Adjuvant Radiation Therapy for Early Stage Anaplastic Large Cell Lymphoma 42

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43 Sonuçlar Characteristic N (%) 2013, 7% 2004, 11% Age < (67) 2012, 10% (33) 2005, 10% Sex Male 570 (60) Female 377 (40) 2011, 8% Charlson-Deyo score (84) (12) 2 36 (4) 2010, 10% 2006, 10% Stage I 405 (43) II 542 (57) 2007, 10% B symptoms Absent 610 (64) Present 228 (24) 2009, 12% 2008, 12% Year of Diagnosis Role of Adjuvant Radiation Therapy for Early Stage Anaplastic Large Cell Lymphoma 44

44 Sonuçlar 903 olgu, % (N=281) konsalidatif RT almış Takip: Median (IQR): 42.8 ( ) ay 45

45 Sonuçlar Factors significant for OS on univariate analysis (p < 0.05) Factors significant for OS on multivariate analysis (p < 0.05) Consolidative RT Younger age Lower Charlson-Deyo score Insurance type Median income Later year of diagnosis Earlier stage Facility type Younger age Lower Charlson-Deyo score Later year of diagnosis Earlier stage Absence of B symptoms Role of Adjuvant Radiation Therapy for Early Stage Anaplastic Large Cell Lymphoma 46

46 5-year OS RT: 78.8% (95% CI: %) Non-RT: 69.4% (95% CI: %) P = 0.02 RT No RT 5-year OS stratified by age Among pts <60 years old, trend toward improved OS with RT P= year OS stratified by Charlson- Deyo score Among pts with Charlson-Deyo score 0, RT improved OS P=0.02 RT No RT 5-year OS stratified by stage Among Stage I pts, RT improved OS P<0.05

47 Sonuçlar Factors significant for receiving consolidative RT by Chi square analysis Earlier year of diagnosis (p=0.03) Stage I (p<0.0001) Absence of B symptoms (p=0.01) Role of Adjuvant Radiation Therapy for Early Stage Anaplastic Large Cell Lymphoma 48

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50 Problem: Tanıdaki PET-CT parametrelerinin prognoz ile ilişkisi? Bulk, SUV Metabolic tumor volume (MTV) Total lesion glycolysis (TLG) The advent of more advanced imaging biomarker or radiomics features allows quantification of detailed tumor radiographic characteristics

51 Hipotez Tanıdaki radiomics Özellikler MTV, TLG, or SUVmax ile birlikte prognostik önem taşıyor mu?

52 Materyal- Metod Çalışmaya dahil edilme kriterleri: Evre I-II HL arası Tek merkezde tedavi edilen Tanıda uygun PET-CT olan olgular

53 Materyal- Metod Hastalık tanımlanması : auto-thresholding tumor - SUV 2.5 1, MIM software Diğer PET parametereleri: SUVmax MTV: disease with SUV TLG: MTV x mean SUV of MTV 34 quantitative radiomics features, reflecting shape, intensity, & texture 1. Freudenberg et al. European Journal of NucMed, 2004

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55 Çalışma Dizaynı: Primer refrakter ve relaps olgularla bu kriterlerin ilişkisi? Mediastinal Lnf olgularında tedavi öncesi risk belirlemede modelleme Model: Makine öğrenme algoritması ve eğitimin validasyonu yaklaşımı Hastalar random olarak 12 gruba ayrılmış: her grupta 1 relaps refrakter hasta 10 eğitim grubu: destek vektör makinesi tabanlı Adaboost Yineleme algoritması geliştirilmiş sınıflandırıcıyı kurdu Kalan 2 group: modeli test etmek ROC eğrileri ile modelin öngörü performansı karakterize ediliyor.

56 Hasta Özellikleri:251 Hasta

57 Sonuçlar: Radiomics Predict 10 Refractory Hst Radiomics features predicted risk of primary refractory disease. But not risk of relapsed disease.

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60 Sonuçlar: Radiomics Mediastinal HL da riskli hastaları öngörü yapabiliyor. Furthermore, this result only valuable for predicting refractory disease in patients with mediastinal disease volume (SUV 2.5) N=169 patients with Stage I-II HL had mediastinal involvement N=12 (7%) had primary refractory disease

61 Sonuç: Model Algoritması 5 önemli Radiomics- Özellikleri tanımlamaktadır Size:3D Volume Intensity:Global Max: SUVmax Heterogeneity: CT texture InverseVariance: measure of heterogeneity range InformationMeasureCorr1: measure of heterogeneity distribution InformationMeasureCorr2: measure of heterogeneity distribution

62 Teşekkürler