IGRT for lung cancer; does XRT dose escalation improve outcome? Jeffrey Bradley, M.D. Associate Professor Department of Radiation Oncology Washington University and The Alvin J. Siteman Comprehensive Cancer Center St. Louis, MO
Topics to discuss Intergroup Trial (RTOG 0617) IGRT Tools for Delivery FDG-PET 4-dimensional CT (x,y,z, and time) Gating Intensity modulation (IMRT) Toxicity Parameters
Randomized Phase III Comparison of Standard Radiotherapy (60 Gy) Vs High-Dose Radiotherapy (74 Gy) with Concurrent and Consolidation Carboplatin and Paclitaxel in Patients with Stage IIIA/IIIB NSCLC RTOG 0617 NCCTG N0628 CALGB 30609 ECOG R0617 www.rtog.org
RTOG 0617 / Intergroup Stratify Initial Design Amendment RT method 3D vs IMRT 60 Gy / 2 Gy 60 Gy with weekly Carbo/paclitaxel Consolidation carbo/paclitaxel x 2 Zubrod PS 0 vs 1 PET Y vs N Histo Sq vs Non Sq Carboplatin and Paclitaxel weekly 74 Gy /2Gy Carboplatin and paclitaxel weekly 60 Gy with weekly carbo/paclitaxel + Cetuximab 74 Gy with weekly carbo/paclitaxel 74 Gy with weekly carbo/paclitaxel + Cetuximab Consolidation Carbo/paclitaxel x 2 Cetuximab Consolidation carbo/paclitaxel x 2 Consolidation Carbo/paclitaxel x 2 Cetuximab
RTOG Intergroup Participation Jeffrey Bradley, MD Hak Choy, MD Gregory Masters, MD Ken Forster, PhD CALGB Jeff Bogart, MD William Blackstock, k MD Mark Socinski, MD NCCTG Steven Schild, MD Alex Adjei, MD, PhD ECOG Christian Dobelbower, MD Tien Hoang, MD Statistics Thomas Pajak, PhD (RTOG) Quality of Life Benjamin Movsas, MD (RTOG) Jeff Sloan, PhD (NCCTG) Translational Joe Y Chang, MD, PhD (RTOG) Outcomes Analysis Joseph O. Deasy, PhD
Primary Objectives To compare overall survival of patients treated with high-dose versus standard dose radiation therapy given with concurrent chemotherapy To compare the overall survival of patients treated with cetuximab versus without cetuximab given with concurrent chemotherapy
Integrating Molecular Targeting Agent with Combined ChemoRT Stage IIIA/B NSCLC: RTOG 0324 Day 1 Cetuximab 400 mg/m 2 IV loading dose Day 8 Cetuximab 250 mg/m 2 wkly/7 Paclitaxel/Carbo l/c RT: 63 Gy Paclitaxel/Carbo X2 Cetuximab Identify Prognostic Indicators 65/93 Tissue Blocks Collected for EGFR (IHC, FISH) Molecular Targeting
RTOG 0324 - Overall Survival 100 % ALIVE 75 50 25 Median survival 22.7 months 2-year survival 49.3% / // 0 0 6 12 18 24 Pts. at Risk MONTHS FROM RANDOMIZATION C225 87 69 59 48 40 Molecular Targeting Blumenschein et al. ASCO 08
Trial Long-term Outcome in LA NSCLC Trials RTOG Trials RT 0324 63 Gy (SDFx) Pac-Carbo/ Carbo/CetuxCetux 0117 74 Gy (SDFx) PAC-CarboCarbo 9801 69.6 Gy (BID Fx) Pac-Carbo/Amifo 9801 69.6 Gy (BID Fx) Pac-Carbo 9410 63 Gy (SDFx) VBL-DDP 9410 63 Gy (SDFx) VBL-DDP 9410 69.6Gy (BID Fx) Chemo Sequence MST 5 yr OS VP-16DDP Ind Induction Con Concurrent Pac Paclitaxel Con-ConsolConsol Con 22.7 m N/A 21.6 m N/A Ind-Con 17.3 17% Ind-Con 17.9 16% Con 17.0 16% Ind 14.6 10% Con 15.1 13% Amif Amifostine VBL vinblastine DDP cisplatin Molecular Targeting
Optimizing Radiotherapy: 60 vs 74 Gy STD dose High Dose VS Tumor = Tumor = 60 cgy* = 74 cgy = *60 Gy to the PTV = 63 Gy to isocenter (9410 dose)
High Dose RT Approaches with ChemoRT Group RTOG 0117* NCCTG N0028* CALGB 30105* UNC* Historic Context RTOG 9410 RT Dose Med Surv 74 Gy 21.6 mo 74 Gy 37 mo 74 Gy 24.6 mo 74 Gy 24 mo 63 Gy 17.1 1 mo * Weekly Paclitaxel/Carbo followed by P/C Physical Targeting
Radiation Techniques for RTOG 0617 Goal: Generate guidelines that incorporate new technology Dose prescribed to the PTV so that 95% of the PTV receives the prescribed dose Heterogeneity corrections required PET or PET/CT RTP encouraged IMRT allowed Tumor motion (one of the following required) ITV method (inhalation/exhalation fusion or 4DCT) Breath hold Gating
60 Gy Dose Question: Red iso = 68 Gy Yellow iso = 63 Gy Green iso = 60 Gy New 60 Gy is similar to the old 63-68 Gy
IMRT allowed (1 st NCI trial) NCI Guidelines - http://rpc.mdanderson.org/rpc/ Protocol must specify patient and tumor immobilization and localization Tumor motion should be 5 5 mm using spirometry, abd compression, 4DCT or inhalation/exhalation h l techniques Protocol provides rationale for IM and SM components of PTV margin Heterogeneity corrected doses Institutional credentialing and central QA
Irradiate Elective Nodes or Not?
Involved Field Radiation Therapy N = 200 pts with Stage III NSCLC randomized to IFRT vs ENI Excluded pts with SC nodes, effusion, KPS <80%, and wt loss >10% 2 cycles of platinum-based chemo, XRT, followed by additional 2-3 cycles same chemo 3D XRT IFRT 68-74 Gy (2 Gy/fx) ENI 60-64 64 Gy (2 Gy/fx) Yuan S et al. AJCO 2007
IFRT vs ENI IFRT ENI p Pneumonitis 17% 29% 0.044 Local failure 41% 49% Elect failure 7% 1 yr Sv 67.2% 59.7% 2yrSv 38.7% 25.6% 0.048 048 3 yr Sv 27.3% 19.2% S. Yuan. AJCO 2007
Involved Field; RTOG 9311 V20 = the % volume of normal lung 20 Gy (normal lung = total lung minus PTV) CTV = GTV PTV = GTV + 10 mm (min 3D margin) ICRU reference in center of PTV 93% isodose to cover PTV (uncorrected for tissue heterogeneity) 8.4 % (15/179) elective nodal failures GTV PTV Bradley. IJROBP 2005 Esophagus
Image-Guided Radiation Therapy (IGRT) FDG-PET 4DCT Daily on-board imaging
Stage Migration with FDG-PET; 1990-99 vs. 2000-0404 N = 3756 patients with NSCLC C at Washington University Goodgame and Govindan. JTO 2008
RTOG 0515 Case 11
4DCT Slide courtesy of Joe Chang, MD, PhD
IGRT: Motion Mgmt for Lung Observe tumor motion in CT simulator 5 mm > 5 mm and > 5 mm and ITV method predictable pattern - Gate or breath hold unpredictable pattern Or cannot breath hold ITV method
Internal Fiducials For gating or breath-hold hold techniques 3DCRT Visicoil or gold beads for mobile tumors SBRT Near chest wall percutaneous placement Central bronchscopic placement kvct performed mostly without fiducials (except for lesions near the diaphragm or mediastinum) kv fluoro (Brainlab, Cyberknife) needs fiducials
On-Board CT Imager (OBI) KV source KV detector Portal imager
Visicoil Fiducials
Radiation Pneumonitis
Pneumonitis, mean dose response - whole lung P robability of pneumonit tis 1.0 MSKCC (10/78) 0.9 Duke (39/201) Michigan (17/109) 0.8 MD Anderson (~49?/223) 0.7 NKI (17/106) WU (52/219) 0.6 Martel et al. (9/42) Oeztel et al. (10/66) 05 0.5 Rancati et al. (7/55) Kim et al. (12/68) 0.4 logistic fit 68% conf envelope 0.3 0.2 0.1 0.0 0 10 20 30 Mean dose (Gy)
Parameter Univariate Correlations Predicting RP 9311 (Spearman s) WU (Spearman s) MLD 0.22 0.18 V 20 0.26 0.18 V 13 0.20 020 0.18 018 D 35 0.20 0.19 D 15 0.28 0.11 GTV-SI 0.13 0.23 GTV-AP 0.06 0.02
Pneumonitis by location RTOG 9311 WU patients WU (n = 228) Figure 3
Bradley and Deasy et al. IJROBP 2007
Does IMRT Help? I think so
WU Data for Local Control 228 patients with non-small cell lung cancer (NSCLC) treated definitively with radiation +/- chemotherapy between 1991-2001 All have: 3D treatment plan archives available Heterogeneity corrected dose distributions Minimum six months follow-up post-treatment treatment unless patient developed pneumonitis
Eligibility Tumor Control Analysis 1991-2001, non-small cell lung cancer Treated definitively, >59 Gy with archived plan Minimum six months follow-up Entire GTV (all eligible) n = 159 TCP endpoint primary or nodal failure Subset isolated peripheral tumors n=57 TCP endpoint primary tumor failure Whole GTV Peripheral primary GTV
Freedom from Local Failure (n=159) 100 95 Dose <66 Gy Dose >66 Gy (%) Surviving 90 85 80 75 70 65 60 55 50 p=0.017 0017 45 0 10 20 30 40 50 60 70 80 Time (months) Hope et al, ASTRO 2005
Tumor position vs. failure Anterior/Posterio tumor position (P=0) 1 0.8 0.6 0.4 0.2 Tumor position Local failure GTV-cord separation (less separation = more failures) Univariate Spearman s rank correlation (Rs) = 0.45 0 0 0.2 0.4 0.6 0.8 1 Right/Left tumor position (R=0)
WU Data. Parameters for local control Parameter Rs (Spearman) P GTV/cord separation 0.45 <0.001 Anterior-posterior tumor position -0.38 0.003 GTV volume -0.37 0.004 GTV V75 0.28 0.04 Prescription dose 0.27 0.04 Age 0.27 0.04
IMRT 3DCRT
IMRT 3DCRT
WU RP Risk Calculator IMRT 3DCRT
Summary 4DCT is an obvious improvement for lung cancer radiotherapy Intergroup Trial (RTOG 0617) ongoing with goal of showing improved survival with high-dose radiation therapy 0617 allows ITV, Gating, and IMRT methods individualized per patient Tools for delivery of high-dose radiotherapy to the thorax are evolving