Review of Workflow NRG (RTOG) 1308: Phase III Randomized Trial Comparing Overall Survival after Photon versus Proton Chemoradiation Therapy for

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1 Review of Workflow NRG (RTOG) 1308: Phase III Randomized Trial Comparing Overall Survival after Photon versus Proton Chemoradiation Therapy for Inoperable Stage II-IIIB NSCLC 1

2 Co-Chairs Study Chair: Zhongxing Liao, MD Radiation Oncology: Jeffrey Bradley, MD, Washington University Noah Choi, MD, Massachusetts General Hospital Steven Hahn, MD, University of Pennsylvania Ritsuko Komaki, MD, MD Anderson Cancer Center Brad Hoppe, MD, University of Florida Eugen Hug, MD, ProCure Medical Oncology: Charles Lu, MD, MD Anderson Medical Physics: Michael Gillin, PhD, MD Anderson Radhe Mohan, PhD, MD Anderson Translational Research: Steven H. Lin, MD, PhD, MD Anderson Quality of Life: Xin Shelley Wang, MD, MD Anderson Outcomes: Ben Movsas, MD, Henry Ford Health System Comparative Cost Effectiveness: Deborah Bruner, RN, PhD, Emory University Gregory Russo, MD, Boston University School of Medicine 2

3 Specific hypotheses When standard constraints on radiation dose and volume to organs at risk (OARs) are used, proton beam therapy will allow lower doses to critical organs and higher doses to be delivered to the target compared with photons, which will result in an improvement of median survival time from 21 months (control arm) to 28 months (proton arm) in patients with good performance status and stage II-IIIB non-small cell lung cancer (NSCLC).

4 RTOG 1308 Schema S T R A T I F Y Stage 1.II 2.IIIA 3.IIIB Histology 1.Squamous 2.Non Squamous Concurrent Chemotherapy Doublet Type 1.Carboplatin/paclitaxel 2.Cisplatin/etoposide R A N D O M I Z E Arm 1: Photon dose 70 Gy*, at 2 Gy (RBE) once daily plus platinumbased doublet chemotherapy** Arm 2: Proton dose 70 Gy (RBE), at 2 Gy once daily plus platinumbased doublet chemotherapy** Both Arms: Consolidation chemotherapy x 2cycles required for patients who receive concurrent carboplatin and paclitaxel*** *The total prescribed dose will be 70 Gy (Relative Biological Effectiveness (RBE)) without exceeding tolerance dose-volume limits of all critical normal structures. (See Section when 70 Gy (RBE) is not achieved) **Chemotherapy delivered concurrently, cisplatin/ etoposide or carboplatin/paclitaxel doublets,isrequired. The site/investigator must declare the chemotherapy regimen that the patient will receive prior to the patient s randomization.see Section 7.0 for details. ***If carboplatin and paclitaxel is administered concurrently with radiotherapy, 2 cycles of carboplatin and paclitaxel consolidation chemotherapy are required. If cisplatin and etoposide is administered concurrently with radiotherapy, consolidation chemotherapy is not allowed. 4

5 Primary Objective To compare the overall survival (OS) in patients with stage II-IIIB NSCLC after image guided, motionmanaged photon radiotherapy (Arm 1) or proton radiotherapy (Arm 2) both given with concurrent platinum- based chemotherapy. Survival time is defined as the time from randomization to the date of death of any cause

6 Secondary Objectives To compare 2-year progression-free survival (PFS) between the 2 arms; To compare the development of grade 3 or higher adverse events definitely, probably, or possibly related to treatment (see Section 13.2 for specific adverse events). To compare the development of patient-reported outcome symptom burden [MDASI-Lung]), Shortness Breath Questionnaire [SOBQ] Health utility EuroQol [EQ5D] To compare cost-effectiveness outcomes To compare pulmonary function changes by treatment arms and response; To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness (imaging, simulation, immobilization, target and critical structure definition, treatment planning, image guidance and delivery).

7 Registration Credentialing Dry run Overall Flow Diagram Enrollment and randomization Radiation Treatment planning Eligibility, IC, PRO, Optional blood Sim and motion management Target Delineation Dose constraints Tumor dose prescriptions Yes Adaptive Planning? Quick review of the plans 1. First (re)plans; 2. Tumor dose <70 Gy Treatment Repeat CT x 2 Weekly AE Wk 4 blood Wk 6 PROs Follow ups 7

8 Registration Credentialing Dry run Overall Flow Diagram Enrollment and randomization Radiation Treatment planning Eligibility, IC, PRO, Optional blood Sim and motion Target Tumor dose Dose constraints management Registrations, sec. 5.0 Delineation : prescriptions Site staff registration with CTEP LOI to NRG (RTOG) Credentialing Yes RT specific pre registration requirements (sec Quick review of the plans ) Adaptive OPEN registration 1. First (re)plans; 2., or Tumor dose <70 Gy Planning? Treatment Repeat CT x 2 Weekly AE Wk 4 blood Wk 6 PROs Follow ups 8

9 Registration Credentialing Dry run Overall Flow Diagram Enrollment and randomization Radiation Treatment planning Eligibility, IC, PRO, Optional blood Patient selection: Refer to protocol sec. 3.0: Sim and motion For questions concerning Target eligibility, please Tumor dose Dose contact constraints RTOG Data Management (via the RTOG management contact list on the Delineation RTOG website) prescriptions Contact or additional? Pretreatment evaluations, protocol sec. 4.0 Informed Yes consent Quick review of the plans Adaptive PRO 1. First (re)plans; 2. Tumor dose <70 Gy Planning? Optional procedures Treatment Repeat CT x 2 Weekly AE Wk 4 blood Wk 6 PROs Follow ups 9

10 Overall Flow Diagram Enrollment and randomization Eligibility, IC, PRO, Optional blood Radiation Treatment planning Sim and motion management Target Delineation Dose constraints Tumor dose prescriptions Quick review of the plans (5 cases) Yes QA Adaptive Planning? Physics QA Peer review QA Treatment Repeat CT x 2 Weekly AE Wk 4 blood Wk 6 PROs Follow ups 10

11 Overall Flow Diagram Radiation Treatment planning Sim RADIATION and motion THERAPY: Target Refer to protocol Dose sec. 6.0: Tumor dose Quick review of the management Data submission: Delineation TRIAD constraints prescriptions plans (5 cases) Dose Specifications, protocol sec. 6.1 as follows: 1. Yes Plan prescription dose 70 Gy, if not QA meeting dose constraints, then 2. Reduce tumor dose 2 Gy each time, i.e. 68, 66, 64, 62, and 60 till dose constraints are met. Adaptive 3. If dose constraints can not be met at 60 Gy, patient Planning? Physics QA Peer review should QA be treated with the highest achievable dose, or start with induction chemotherapy if patient had not received induction chemotherapy Simulation, Immobilization, Motion Treatment Assessment, and Motion Management, sec. 6.3 Repeat CT x 2 Weekly AE Wk 6 PROs Follow ups Target Definitions, Target Delineation, and Normal Anatomy Delineation, sec 6.4 Required structures should we standardize the color? Optional procedures Wk 4 blood 11

12 Overall Flow Diagram Radiation Treatment planning Sim and motion Target Dose Tumor dose Quick review of the management Delineation constraints prescriptions plans (5 cases) RADIATION THERAPY: Refer to protocol sec. 6.0: Data submission: TRIAD Dose Yes Specifications, protocol sec. 6.1 QA as follows: 1. Plan prescription dose 70 Gy, if not meeting dose constraints, then Adaptive 2. Reduce tumor dose 2 Gy each time, i.e. 68, 66, 64, 62, and 60 till dose constraints are Planning? met. Physics QA Peer review QA 3. If dose constraints can not be met at 60 Gy, patient should be treated with the highest achievable dose, or start Treatment with induction chemotherapy if patient had not received induction chemotherapy Repeat Simulation, CT x 2 Immobilization, Weekly AE Motion Assessment, and WkMotion 6 PROs Management, Follow ups sec. 6.3 Wk 4 blood 12

13 Motion Management Strategy example of 4D CT 13

14 Example of Simulation for Breath Hold treatment Does the tumor move enough to justify BH treatment Can the patient follow instructions for a >15 sec BH Does the tumor reproduce to the same position (based on 5 10 repeated video feedback guided breath hold scans) What is the patient specific IM among a series of breath holds P. Balter 14

15 Overall Flow Diagram Radiation Treatment planning RADIATION THERAPY: Refer to protocol sec. 6.0: Sim and motion Target Dose Tumor dose Quick review of the Data submission: Delineation TRIAD management constraints prescriptions plans (5 cases) Dose Specifications, protocol sec. 6.1 as follows: 1. Plan prescription dose 70 Gy, if not meeting dose constraints, Yes 1. Submit the case to RTOG headquarters QA for review and suggestions, if still not meeting dose constraint Adaptive 2. Reduce tumor dose 2 Gy each time, i.e. 68, 66, 64, 62, and 60 till dose constraints Planning? are met. Physics QA Peer review QA 2. If dose constraints can not be met at 60 Gy, patient should be treated with the highest achievable dose, or start with induction chemotherapy if patient had not received induction chemotherapy Treatment Repeat Simulation, CT x 2 Immobilization, Weekly AE Motion Assessment, and WkMotion 6 PROs Management, Follow ups sec. 6.3 Target Definitions, Target Delineation, and Normal Anatomy Delineation, sec 6.4 Required structures should we standardize the color? Wk 4 blood 15

16 Standardization on Colors Structure DICOM Standard Name Gross Tumor Volume GTV RED GTV plus margin for tumor motion IGTV RED Clinical Target Volume CTV YELLOW Internal Target Volume ITV YELLOW Planning Target Volume PTV Spinal Cord SpinalCord Right + Left Lung minus GTV Lungs Right Lung Lung_R Left Lung Lung_L Esophagus Esophagus Brachial Plexus BrachialPlexus Heart Heart Liver Liver Brown Right Kidney Left Kidney Kidney_R Kidney_L Orange 16

17 Proposed DVH Constraints with New Rec on Heart Normal lung (right lung V + left lung V GTV) Per Protocol V20 37%; MLD 20 Gy (RBE); lung V5 60% Variation Acceptable* V20 40 % or MLD 22 Gy (RBE); lung V5 65% Esophagus Max dose: 74 Gy (RBE) 1cc of partial circumference Max dose: 74 Gy (RBE) 1.5 cc of partial circumference V cc V cc V cc V cc V cc V cc V cc V cc Spinal cord*** V50 < 0.03 cc V52< 0.03 cc Brachial plexus** Heart V30 50% V45 35% Max Dose to a point that is 0.03 cc 70 Gy V30 55% V45 40% Max Dose to a point that is 0.03 cc 75 Gy**** 17

18 Plan Review Criteria Cover 95% of the PTV with the prescription dose. <= 0.03 cc inside PTV should exceed 120% of the prescribed dose. Cover 100% of the ITV Variation Acceptable: 95% of the PTV is covered by 95% of the prescription dose, <= 0.03 cc inside the PTV >120% <=125% of the prescribed dose; <=0.03 cc <85% >=75% of the prescription dose; <100% but >=99% of the ITV is covered by the prescription dose Deviation Unacceptable: A Deviation Unacceptable occurs when any of the Variation Acceptable dose limits stated above are not met 18

19 Overall Flow Diagram Radiation Treatment planning Sim and motion management Target Delineation Dose constraints Tumor dose prescriptions Quick review of the plans (5 cases) Yes Adaptive Planning? 4DCT is repeated at the end of week 2 and mid-week 5 QA Anatomy review is performed first Dosimetric review (recalculation of original plan on new anatomy) is requested when Physics QA Peer review there QA is significant changes Replan if necessary Treatment Repeat CT x 2 Weekly AE Wk 4 blood Wk 6 PROs Follow ups 19

20 Overall Flow Diagram Radiation Treatment planning Sim Quick and review motion of the plans Target and replans: Dose Tumor dose management Refer to protocol Delineation constraints prescriptions Case submitted refer to Ying Xiao, presentation for Yes TRIAD system QA PI or designee notified (Liao, Hoppe, Bradley, Adaptive etc) Planning? Feedback send Physics to submitting QA institutionpeer review QA If plan good move to treat the patient If plan needs revision, repeat Treatment above steps Repeat CT x 2 Weekly AE Wk 4 blood Wk 6 PROs Quick review of the (re)plans (3 cases) Follow ups 20

21 Questions? 21