BEST of ASTRO 2016 Akciğer Kanseri. Dr. Serap Akyürek Ankara Üniversitesi Tıp Fakültesi Radyasyon Onkolojisi Anabilimdalı

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1 BEST of ASTRO 2016 Akciğer Kanseri Dr. Serap Akyürek Ankara Üniversitesi Tıp Fakültesi Radyasyon Onkolojisi Anabilimdalı

2 Plan YE-KHAK konsolidasyon RT için hasta seçimi? Evre III KHDAK SIB ile RT doz artım çalışması KHDAK de küratif tedavi sonrası rekürrensi, görüntüleme izlemi ile saptama vs semptom ile saptama Torakal vertebra RT dozu ile akut hematolojik toksite

3 Identifying patients with extensive stage small cell lung cancer (SCLC) most likely to benefit from intensive radiotherapy Ben Slotman, Corinne Faivre-Finn, Harm van Tinteren, Astrid Keijser, John Praag, Joost Knegjens, Matthew Hatton, Iris van Dam, Annija van der Leest, Bart Reymen, Jos Stigt, Kate Haslett, Devashishi Tripathi, Egbert Smit, Suresh Senan Department of Radiation Oncology VUmc, Amsterdam, The Netherlands

4 First Study: Consolidative Thoracic RT in Extensive Stage Small Cell Lung Cancer ED-SCLC 3 cycles PE CR - extra-thoracic disease CR/PR - thoracic disease ACC HFX RT/ChT 54 Gy in 18 days PE x 2 PCI PE x 2 Jeremic B et al. JCO 17(7): , 1999

5 First Study: Consolidative Thoracic RT in Extensive Stage Small Cell Lung Cancer ACC HFX RT/ChT 54 Gy in 18 days ED-SCLC 3 cycles PE 109 patients CR - extra-thoracic disease CR/PR - thoracic disease Med Survival Time: 17 versus 11 months 5-year OS 9.1% versus 3.7% PE x 2 PCI PE x 2 Jeremic B et al. JCO 17(7): , 1999

6 PCI in ES SCLC study

7 CREST trial: Design ES-SCLC No brain- /leptomeningeal mets No pleural mets No previous RTX brain/thorax Any response after 4-6 cycles of platinum-based chemotherapy WHO 0-2 Age 18+ Encompassable volume Arm A R Arm B PCI + TRT (10x 3 Gy) Stratification: Residual intrathoracic disease Institution PCI Slotman et al., Lancet 2015, 385, Study treatment should start between 2 and 7 weeks after last chemotherapy

8 CREST trial: PFS & OS Progression-free survival Overall survival HR = 0.73 (p=0.001) HR = 0.84 (p=0.066) Slotman et al., Lancet 2015, 385, At 24 months (p=0.004) Thoracic RT arm 13% Control arm 3%

9 Residual Intrathoracic Disease Slotman et al., Lancet 2015, 385, With residual intrathoracic disease 95% CI OS P<0.05 PFS P<0.001 Without residual intrathoracic disease OS N.S. PFS N.S.

10 Overall Survival (Patients with Residual Thoracic Disease) 1.0 Thoracic RT No Thoracic RT months Survival Probability months HR= 0.81 log-rank p- HR =0.81 (95%CI ) p< Months Thoracic RT No Thoracic 219 RT Slotman et al., Lancet 2015, 385,

11 Recurrences PCI only (n=248) PCI + TRT (n=247) None 10.1% 13.8% Brain 5.2% 9.7% Thorax 79.8% 43.7% Outside thorax and brain 40.5% 60.3%

12 The next step after the CREST-trial TRT led to improved PFS and OS in patients with residual intrathoracic disease after chemotherapy However, after 30 Gy/10fx TRT still 44% intrathoracic recurrence: Higher TRT dose? 60% develops progression outside the brain Radiotherapy to other sites of diseases?

13 NRG Oncology RTOG 0937 ED-SCLC 1-4 metastatic lesions No brain metastases 4-6 cycles platinum based chemotherapy CR or PR (no progression) Stratify CR vs PR 1 vs 2-4 metastatic lesions Age <65 vs > 65 years* PCI 25 Gy in 10 fractions PCI + Extra-cranial RT Primary and regional nodes Metastatic disease Gy in fractions

14 RTOG 0937: Overall Survival HR 1.44 (95% CI: ) 1yr OS: 60.1% vs 50.8% 1 y GS %60.1 vs %50.8 p=0.2 2

15 RTOG 0937: Worst AE per Patient (Any) CTCAE v4 PCI PCI+RT Non-Hematologic Grade 1 11 (26.2%) 9 (20.5%) 2 14 (33.3%) 15 (34.1%) 3 9 (21.4%) 10 (22.7%) 4 1 (2.4%) 1 (2.3%) (9.1%) Any Grade 1 11 (26.2%) 9 (20.5%) 2 14 (33.3%) 14 (31.8%) 3 9 (21.4%) 9 (20.5%) 4 1 (2.4%) 3 (6.8%) (9.1%)

16 RTOG 0937: Grade 5 Toxicity in the PCI+RT Arm Event Relationship to Tx Days from last Tx Event Relationship Relation-ship to Tx Days from Days last from last Tx to Tx treatment Cardiac Cardiac Arrest/?PE Unrelated Cardiac Arrest/?PE Unrelated 95 New New Malignancy 25 New Malignancy Malignancy Unrelated Unrelated Pneumonitis Unrelated 126 Pneumonitis Pneumonitis Unrelated Unrelated 126 Respiratory Failure Definite 108 Respiratory Respiratory Failure Failure Definite Definite 108 V20 = 37.4% V5 = 86.6% MLD = 17.7 Gy

17 RTOG 0937: Failure Patterns PCI PCI+RT Chest 20 (62.5%)* 8 (25.8%) Presenting Disease 25 (78.1%) 13 (41.9%)** New Disease 10 (31.3%) 19 (61.3%)

18 Identifying patients with extensive stage small cell lung cancer (SCLC) most likely to benefit from intensive radiotherapy Which patients are most likely to benefit from more agressive radiotherapy PCI plus higher TRT and extrathoracic RT Additional patient data was collected from top 9 recruiting center in randomized CREST trial 260 patients (%53 of 495 study patients) were analyzed

19 Patients characteristics (n=260)

20 Number and sites of metastases

21 Number and sites of metastases: Overall survival 0-2 metastases 3 metastases 0-2 metastases 3 metastases Nr. of metastases 0-2 vs 3 HR 1.43 (95%CI: ) P=0.02 Liver metastases Absent/Present HR 1.34 (95%CI: ) P=0.03 Bone metastases Absent/Present HR 1.33 (95%CI: ) P=0.04

22 Effect of TRT and Liver Metastases Without liver metastases (n=139) OS HR=1.38 (p=0.08) PFS HR =1.74 (p=0.001) PFS - Without liver mets With liver metastases (n=121) OS: HR=0.90 (p=0.57) PFS HR=1.22 (p=0.28)

23 Authors Conclusions Future studies on more intensive thoracic and extrathoracic radiotherapy in ES-SCLC should preferably focus on patients with a maximum of two metastases and without liver metastases.

24 RT in Extensive Stage Small Cell Lung Cancer PCI is standard (level I evidence) Thoracic RT lowers local recurrence, but survival benefit uncertain Patients with residual disease after chemotherapy get most benefit Optimal dose not defined Radiation therapy of extrathoracic sites remains investigational and may be associated with additional toxicity.

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26 Safety of Dose Escalation by Simultaneous Integrated Boosting Radiation Dose in Unresectable Stage III Non-small-cell Lung Cancer Qin Zhang, Xiao-long Fu, Xu-wei Cai, Wen Feng Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China

27 RTOG0617: Background Concurrent chemoradiotherapy: 60Gy VS 74Gy Randomozation Chemo X RT (60Gy) Chemo X RT (60Gy) +Cetuximab Chemo X RT (74Gy) Chemotherapy Chemotherapy(60Gy) +Cetuximab Chemotherapy Bradley, J. D.; Paulus, R.; Komaki, R,Lancet Oncol, 2015, 16(2),

28 Purpose To determine the maximum-tolerable dose of hypofractionated radiotherapy (RT) with concurrent chemotherapy (CT), and evaluate the safety of dose escalation by simultaneous integrated boosting (SIB) radiation dose in unresectable stage III NSCLC.

29 Methods/Materials Radiotherapy: GTV:The primary tumor +all involved nodes CTV:GTV cm PTV-G:GTV+0.8 cm PTV-C: CTV +0.8 cm Spinal Cord 45 Gy Lung V20 25%; MLD(lung) 15 Gy MHD( heart ) 30 Gy. Chemotherapy: Cisplatin(20 mg/m 2 d1) Docetaxel (20 mg/m 2 d1) weekly, 6 cycles

30 Methods/Materials DOSE LEVEL PTV-G PTV-C 1 60Gy/30Fx(2Gy/Fx) 54Gy/30Fx(1.8Gy/Fx) 2 60Gy/24Fx(2.5Gy/Fx) 50.4Gy/24Fx(2.1Gy/Fx) Gy/22Fx(2.75Gy/Fx) 49.5Gy/22Fx(2.25Gy/Fx) 4 60Gy/20Fx(3Gy/Fx) 50Gy/20Fx(2.5Gy/Fx)

31 Results From April 2012 to October 2013 dose has been escalated up to LEVEL 4 (PTV-G60Gy/20Fx, PTV-C50Gy/20Fx) DOSE LEVEL PTV-G PTV-C NO. 1 60Gy/30Fx(2Gy/Fx) 54Gy/30Fx(1.8Gy/Fx) Gy/24Fx(2.5Gy/Fx) 50.4Gy/24Fx(2.1Gy/Fx) Gy/22Fx(2.75Gy/Fx) 49.5Gy/22Fx(2.25Gy/Fx) Gy/20Fx(3Gy/Fx) 50Gy/20Fx(2.5Gy/Fx) 10

32 Grade I- II(%) Grade III-IV(%) Grade IV(%) Dose LEVEL1 5pts Hematologic toxicity 3 Gastrointestinal toxicity 2 Radiation Esophagitis 2 1 Radiation Pneumonitis 4 Results: Toxicity Dose LEVEL2 5pts Hematologic toxicity 2 Gastrointestinal toxicity 2 Radiation Esophagitis 2 1 Radiation Pneumonitis 2 Dose LEVEL3 5pts Hematologic toxicity 3 Gastrointestinal toxicity 1 Radiation Esophagitis 3 Radiation Pneumonitis 3 Dose LEVEL4 10pts Hematologic toxicity 6 1 Gastrointestinal toxicity 4 2 Radiation Esophagitis 5 Radiation Pneumonitis One patient at LEVEL 4 died of upper gastrointestinal hemorrhage 5 additional patients were enrolled at this level to ensure safety of this trial

33 Results Median follow-up time: 27.3 months (range, ) Median PFS 15.4 m Median OS 27.3m 1-year and 2- year local control was 69.8% and 60.5%,respectively

34 Conclusions Dose escalation in unresectable stage III NSCLC has been safely achieved up to LEVEL 3 (PTV-G 60.5Gy/22Fx, 2.75Gy/Fx; PTV-C 49.5Gy/22Fx, 2.25Gy/Fx) Acute toxicities were well tolerable, further investigations should focus on late toxicities. It is a feasible therapeutic approach for unresectable stage III NSCLC and may provide encouraging locoregional control with a low toxicity profile.

35 Safety of Dose Escalation by Simultaneous Integrated Boosting Radiation Dose in Unresectable Stage III Non-small-cell Lung Cancer MTD Zhang et al 60.5Gy/22 to GTV 78.85Gy BED10 RTOG Gy/37fr 88.8Gy BED10 Standard 60Gy/30fr 72Gy BED10 LC ve OS fark yok ancak tedavi süresinin kısa olması uygulanabilir görünmekte!!!

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37 Radiation Dose to the Thoracic Vertebral Bodies is Associated with Acute Hematologic Toxicity in Patients Receiving Concurrent Chemoradiation for Lung Cancer Christian L. Barney, Nicholas Scoville, Karl E. Haglund, John Grecula, E. Terence Williams, Meng Welliver, Jose G. Bazan The Ohio State University

38 Chemoradiation (CRT) for Lung Cancer is Toxic Most common grade 3 acute toxicity is hematologic Reported grade 3 neutropenia as high as 82% Consequences: Chemotherapy (CTX) dose reductions and treatment breaks Hospitalizations Infection Transfusion requirements

39 The Role of Radiation in Hematologic Toxicity is Poorly Understood Recent published data suggest that irradiation of thoracic vertebral body (TVB) bone marrow may correlate with acute hematologic toxicity (HT) in CRT for non-small cell lung cancer (NSCLC). Constraints for TVBs are not establis

40 Purpose To identify TVB dosimetric parameters that correlate with HT in a large cohort of patients undergoing CRT for lung cancer. To identify dosimetric cut-points in TVB for organ at risk constraint utility.

41 Patient Treatment Characteristics 218 patients treated with definitive CRT for lung cancer median (range) RT total dose (Gy) 60 (45-70) RT fractions (#) 30 (25-54) n (%) RT technique IMRT 165 (76) 3D-conformal 53 (24) Chemotherapy Cisplatin/etoposide 115 (53) Carboplatin/paclitaxel 96 (44) Other 7 (3) Induction 47 (22)

42 Bone Marrow Delineation External contour of T1 - T10 vertebral bodies was used as a surrogate for vertebral body bone marrow

43 Results: Odds of Grade 3+ Hematologic Toxicity Mean Dose and lowdose parameters did correlate with HT3+ IMRT was trending No correlation with chemotherapy variables Univariate Analysis of Parameters Associated with HT3+ Odds Ratio (95% CI) p-value Mean Dose (per Gy) ( ) V5 (per %) ( ) V10 (per %) ( ) V20 (per %) ( ) V30 (per %) ( ) V40 (per %) ( ) V50 (per %) ( ) 0.10 V60 (per %) ( ) Age ( ) ECOG PS ( ) IMRT ( ) BMI ( ) Cisplatin vs other ( ) Induction CT ( ) 0.168

44 Results: Odds of Grade 3+ Hematologic Toxicity Mean and lowdose correlates for HT3+ persisted when adjusting for other potential confounders (Age, BMI, and IMRT) Multivariate Analysis of Parameters Associated with HT3+ Odds Ratio (95% CI) p-value Mean Dose (per Gy) ( ) V5 (per %) ( ) V10 (per %) ( ) V20 (per %) ( ) Ranges Odds Ratios p-values Age BMI IMRT

45 Results: Dose Cut-points Mean and low-dose optimal cut-points correspond with ~2-fold increase in HT3+ Optimal Cut-point OR (95% CI) p-value Mean Dose 23Gy 1.78 ( ) V5 65 % 2.08 ( ) V10 60 % 2.08 ( ) V20 50 % 1.78 ( ) 0.038

46 Conclusions Mean dose to the vertebral bodies and low-dose parameters (V5, V10, V20) correlate with HT3+ Low-dose bath of IMRT may contribute to this effect V5=65%, V10=60%, V20=50% and mean dose of 23 Gy correlate with ~2-fold increase in HT3+ Minimizing low dose and mean dose to the TVBs may reduce the rate of severe HT in patients receiving CRT for lung cancer.

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48 Role of Surveillance Imaging versus Symptoms and Signs in Detection of Recurrence of Non-Small Cell Lung Cancer After Curative Intent Therapy Sarah Waliany, Michael Gensheimer, Rie von Eyben, David Shultz, Billy Loo, Maximilian Diehn Department of Radiation Oncology, Stanford School of Medicine

49 Background: Detection of NSCLC Recurrence NCCN guidelines for NSCLC recommend post-treatment surveillance imaging every 6-12 months for 2 years followed by annual scans Symptoms and physical exam signs are predominant detectors of recurrence in Non-Hodgkin s Lymphoma. Limited data comparing imaging with symptoms/signs for recurrence detection in NSCLC Truong et al, Clin Lymphoma Myeloma Leuk 2014; Goldschmidt et al, Ann Hematol 2011; Elis et al, Am. J. Hematol 2002

50 Objectives Determine value of surveillance imaging (Chest CT and/or PET/CT), self-reported symptoms and physical exam signs in recurrence detection in NSCLC Compare survival outcomes by modality of recurrence detection (imaging versus symptoms/signs)

51 Characterization of Recurrence Post-treatment surveillance for Stage I-III NSCLC + met inclusion criteria: N = 508 Recurrence: N = 203 No recurrence: N = 305 Site of recurrence: locoregional (LR) or distant (DR) Modality of recurrence detection: imaging versus symptoms/signs Date of recurrence detection

52 Patient Demographic and Clinical Characteristics

53 Recurrence Type and Detection Modality

54 Recurrence Type and Detection Modality

55 Recurrence Type and Detection Modality

56 Factors Associated with Differences in Recurrence Detection Modality

57 Survival Differences by Recurrence Type in Patients with Imaging-Detected Recurrence Post-Recurrence Survival (%) P=0.038 Distant (N = 61) Locoregional (N = 86) Time from Recurrence (Months)

58 Survival Differences by Recurrence Detection Modality in Patients with Distant Recurrence Post-Treatment Survival (%) Symptom/Sign (N = 54) P=0.038 Imaging (N = 61) Post-Recurrence Survival (%) Symptom/Sign (N = 54) P=0.096 Imaging (N = 61) Time from End of Treatment (Months) Time from Recurrence (Months)

59 Kernel Smoothing Method: Hazard Function of Recurrence Smoothed Hazard of Recurrence 24% of all recurrences detected by 6 months 53% detected by 12 months 83% detected by 24 months 91% detected by 30 months Time to Recurrence (Months)

60 Kernel Smoothing Method: Hazard Function of Recurrence Smoothed Hazard of Recurrence 24% of all recurrences detected by 6 months 53% detected by 12 months 83% detected by 24 months 91% detected by 30 months Time to Recurrence (Months)

61 Summary of Findings Most locoregional recurrences (LR) are detected by imaging whereas distant recurrences are detected equally frequently by imaging as by symptoms/signs. Recurrences detected by imaging had better post-treatment survival and postrecurrence survival (PRS) than those detected by symptoms/signs. Imaging-detected LR: 3-year PRS rate of 37% Imaging-detected DR: 3-year PRS rate of 28% Symptom-detected DR: 3-year PRS rate of 10% Suggests importance of surveillance imaging in improving outcomes by detecting treatable locoregional recurrences.

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