ASTRO Andrew J. Hope, M.D.

Transcription

1 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

2 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

3 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 ECOG R0617

4 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

5 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

6 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

7 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

8 RTOG Overall Survival 100 % ALIVE Median survival 22.7 months 2-year survival 49.3% / // Pts. at Risk MONTHS FROM RANDOMIZATION C Molecular Targeting Blumenschein et al. ASCO 08

9 Trial Long-term Outcome in LA NSCLC Trials RTOG Trials RT Gy (SDFx) Pac-Carbo/ Carbo/CetuxCetux Gy (SDFx) PAC-CarboCarbo Gy (BID Fx) Pac-Carbo/Amifo Gy (BID Fx) Pac-Carbo Gy (SDFx) VBL-DDP Gy (SDFx) VBL-DDP Gy (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 % Ind-Con % Con % Ind % Con % Amif Amifostine VBL vinblastine DDP cisplatin Molecular Targeting

10 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)

11 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 mo * Weekly Paclitaxel/Carbo followed by P/C Physical Targeting

12 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

13 60 Gy Dose Question: Red iso = 68 Gy Yellow iso = 63 Gy Green iso = 60 Gy New 60 Gy is similar to the old Gy

14 IMRT allowed (1 st NCI trial) NCI Guidelines - 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

15 Irradiate Elective Nodes or Not?

16 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 Gy (2 Gy/fx) ENI Gy (2 Gy/fx) Yuan S et al. AJCO 2007

17 IFRT vs ENI IFRT ENI p Pneumonitis 17% 29% Local failure 41% 49% Elect failure 7% 1 yr Sv 67.2% 59.7% 2yrSv 38.7% 25.6% yr Sv 27.3% 19.2% S. Yuan. AJCO 2007

18 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

19 Image-Guided Radiation Therapy (IGRT) FDG-PET 4DCT Daily on-board imaging

20 Stage Migration with FDG-PET; vs N = 3756 patients with NSCLC C at Washington University Goodgame and Govindan. JTO 2008

21 RTOG 0515 Case 11

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24 4DCT Slide courtesy of Joe Chang, MD, PhD

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27 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

28 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

29 On-Board CT Imager (OBI) KV source KV detector Portal imager

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32 Visicoil Fiducials

33 Radiation Pneumonitis

34 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) Rancati et al. (7/55) Kim et al. (12/68) 0.4 logistic fit 68% conf envelope Mean dose (Gy)

35 Parameter Univariate Correlations Predicting RP 9311 (Spearman s) WU (Spearman s) MLD V V D D GTV-SI GTV-AP

36 Pneumonitis by location RTOG 9311 WU patients WU (n = 228) Figure 3

37 Bradley and Deasy et al. IJROBP 2007

38 Does IMRT Help? I think so

39 WU Data for Local Control 228 patients with non-small cell lung cancer (NSCLC) treated definitively with radiation +/- chemotherapy between All have: 3D treatment plan archives available Heterogeneity corrected dose distributions Minimum six months follow-up post-treatment treatment unless patient developed pneumonitis

40 Eligibility Tumor Control Analysis , 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

41 Freedom from Local Failure (n=159) Dose <66 Gy Dose >66 Gy (%) Surviving p= Time (months) Hope et al, ASTRO 2005

42 Tumor position vs. failure Anterior/Posterio tumor position (P=0) Tumor position Local failure GTV-cord separation (less separation = more failures) Univariate Spearman s rank correlation (Rs) = Right/Left tumor position (R=0)

43 WU Data. Parameters for local control Parameter Rs (Spearman) P GTV/cord separation 0.45 <0.001 Anterior-posterior tumor position GTV volume GTV V Prescription dose Age

44 IMRT 3DCRT

45 IMRT 3DCRT

46 WU RP Risk Calculator IMRT 3DCRT

47 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