Particle Therapy for Lung Cancer. Bradford Hoppe MD, MPH Assistant Professor University of Florida
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1 Particle Therapy for Lung Cancer Bradford Hoppe MD, MPH Assistant Professor University of Florida
2 Content Rationale for Particle Therapy in Lung Cancer Proof of Principle Treatment Planning Challenges
3 Siegel et al. CA: A Cancer Journal for Clinicians 2012 Background
4 5- year Overall Survival Rates Stage Lung Cancer 1 50% 2/3 15% 4 3% Siegel et al. CA: A Cancer Journal for Clinicians 2012
5 5 yr- Overall Survival Rates Stage Lung Prostate Breast 1 50% 100% 98% 2/3 15% 100% 84% 4 3% 30% 24% Siegel et al. CA: A Cancer Journal for Clinicians 2012
6 Lung Cancer Non-Small Cell Lung Cancer~85% Small Cell Lung Cancer~15%
7
8 Lung Cancer Non-Small Cell Lung Cancer Small Cell Lung Cancer
9 Stage I Non-Small Cell Lung Cancer
10 Stage I NSCLC Treatment Grutters et al Radiotherapy Oncology yr OS (95%CI) Conventional RT 20% (15-24%)
11
12 Stage I NSCLC Treatment Grutters et al Radiotherapy Oncology yr OS (95%CI) Conventional RT 20% (15-24%) Proton Therapy 40% (25-55%) Carbon Therapy 42% (32-52%)
13 Stage I NSCLC Author N= FU Dose fractions LC OS Bush et al 1999 & Gy 10 3yr- 74% 3yr- 44% Shioyama et al Gy yr-89%/39% 5yr- 70%/16% Nihei et al Gy 20 2yr- 80% 2yr-84% Hata et al Gy 10 2yr- 95% 2yr- 74% Nakayama et al Gy 72.6 Gy yr- 97% 2yr- 98% Chang et al Gy 35 2yr- 89% 2yr- 55% Westover et al Gy 3-5 2yr- 100% 2yr-64% Iwata et al Gy Gy 10 3yr-82% 3yr-75% Gy 4 Miyamoto et al Gy Gy % 97% 5yr- 42% Miyamoto et al Gy 9 5yr- 95% 5yr- 50% Miyamoto et al Gy 4 3yr- 90% 3yr- 60% Proton therapy Carbon therapy
14 Stage I NSCLC Treatment Grutters et al Radiotherapy Oncology yr OS (95%CI) Conventional RT 20% (15-24%) Proton Therapy 40% (25-55%) Carbon Therapy 42% (32-52%) Stereotactic Ablative Body Radiotherapy (SABR) 42% (34-50%)
15 Stage I NSCLC Grutters et al Radiotherapy Oncology Grade 3 or higher toxicity Treatment Pneumonitis Dyspnea Esophagitis Death Conventional RT 0.2% 0.5% 0.1% 0.1% Proton Therapy 0.8% Carbon Therapy 1.4% 0 NA 0 SABR 2% 0.8% 0.2% 0.7%
16 Dosimetry: Protons vs SABR for Stage I Group Reference Stage Vienna Georg Radiother Oncology 2008 IA Mayo Macdonald IJROBP 2009 I UF Hoppe Radiother Oncology 2010 I MDACC Register IJROBP 2011 I STPTC (Japan) Kadoya IJROBP 2011 I
17 Dosimetry: Protons vs SABR for Stage I Mean lung Lung V5 Lung V20 Dose Xrays Protons Xrays Protons Xrays Protons University Vienna* 45 Gy 3.9 Gy 3 Gy 17% 10% 6% 8% Mayo** 60 Gy 3.8 Gy 3.3 Gy 18% 11% 4% 6% University of Florida + 48 Gy 5.7 Gy 3.9 Gy 22% 14% 10% 8% MD Anderson Gy 5.4 Gy 3.5 Gy 23% 11% 9% 7% Nagoya University Gy 7.8 Gy 4.6 Gy 32% 13% 11% 9% *Georg et al Radiotherapy and Oncology 2008 **MacDonald et al IJROBP Hoppe et al Radiotherapy and Oncology Register et al IJROBP Kadoya et al IJROBP 2011 SABR-PT Average difference in: mean lung dose = 1.7 Gy lung V5 = 10% lung V20 = 1%
18 Dosimetry: Protons vs SABR for Stage I Group Reference Stage Benefit Vienna Georg Radiother Oncology 2008 IA None Mayo Macdonald IJROBP 2009 I None UF Hoppe Radiother Oncology 2010 I Bigger tumors benefit Register IJROBP 2011 MDACC I Central/Superior tumors benefit STPTC (Japan) Kadoya IJROBP 2011 I Bigger tumors & multiple tumors
19 Smaller tumors Benefit Georg Radiotherapy Oncology 2008
20 Bigger tumors Benefit IMRT PROTONS
21 Bigger tumors Benefit IMRT Protons Mean lung 19 Gy 11 Gy Mean esophagus 22 Gy 7 Gy Mean heart 35 Gy 13 Gy
22
23 Central tumors Benefit Protons SABR
24 SBRT Protons Mean lung 10 Gy 5 Gy Lung V20 17% 10% Mean esophagus 6 Gy 5 Gy Mean heart 10 Gy 0.2 Gy
25 PT > SABR Stage I Non-Small Cell Lung Cancer Larger tumors Centrally located tumors Superior located tumors (brachial plexus) Multiple tumors (re-irradiation)
26 Stage II/III Non-Small Cell Lung Cancer
27 Background 2: Cisplatin/vinblastine + 63Gy (daily) Median OS-17 months 1: Cisplatin/vinblastine followed by 63 Gy (daily) Median OS months
28 Stage II/III NSCLC RTOG Study RT Dose Med OS Gd3+ GI Gd3+ Lung Gy+ ENI 17 months 23% 15% Local Control rates of ~40%
29 Stage II/III NSCLC RTOG Study RT Dose Med OS Gd3+ GI Gd3+ Lung Gy+ ENI 17 months 23% 15% Gy 26 months 24% 16%
30 Stage II/III NSCLC RTOG Study RT Dose Med OS Gd3+ GI Gd3+ Lung Gy+ ENI 17 months 23% 15% Gy 26 months 24% 16% Gy 29 months All Gd 3+ 74% 74Gy 20 months All Gd 3+ 76%
31 Stage III NSCLC (n=57) Carbo/Taxol Gy (ENI) Surgery (n=37) Complete Response (n=3) <CR (n=34)
32 RTOG 0617 MVA- Lower heart V5 associated with better OS
33 Stage IIIA- Nichols CLC DCRT IMRT PT
34 Dosimetric Advantage for Stage III Lung Mean lung Lung V5 Lung V20 Dose 3D IMRT Protons 3D IMRT Protons 3D IMRT Protons Chang 74 Gy 25 Gy 24Gy 20 Gy 58% 62% 40% 40% 37% 32% Nichols 74 Gy 21 Gy 15Gy 11 Gy 54 % 50% 32% 27% 27% 21% Nichols ENI 74/40 20 Gy 16Gy 13 Gy 53% 51% 31% 30% 26% 24% Zhang 74 Gy NA 20Gy 15 Gy NA 59% 39% NA 35% 28% Vogelius 60 Gy 12Gy 10Gy 5 Gy NA NA NA 22% 14% 10% Double scatter PT IMPT DS Protons reduced Mean Lung Lung V5 Lung V20 3DCRT 7 Gy 20% 7% IMRT 4 Gy 20% 5%
35 Dosimetric Advantage for Stage III Heart & Esophagus Heart V40/mean dose Esophagus V55/ mean dose Dose 3D IMRT Protons 3D IMRT Protons Chang 74 Gy 29% 12% 8% 41% 37% 36% Nichols 74 Gy 11 Gy 6 Gy 4 Gy 44Gy 32Gy 29 Gy Nichols ENI 74/40 NA 9 Gy 4 Gy 27Gy 26Gy 25 Gy Zhang 74 Gy NA 22% 8% NA 32% 25% Double scatter PT IMPT
36 Stage II/III NSCLC clinical studies Author N= FU Dose DFS OS LC GI tox Lung tox Bush Gy-PT, 45Gy XRT 2yr- 19% 2yr- 13% Shioyama 2003 Nakayama 2011 Oshiro 2012 Chang Gy/ fx (XRT+PT) Gy/ fx Gy Gy/ 37 fx + Chemo 2yr- 71%; 5yr-0% 2yr-29% 2yr-59% 11% 0% 0% 2yr- 25% 2yr- 39% 16% 0% 5%/8% 2yr- 48% 2yr- 55% 20% 11% 5% Hoppe Gy + chemo Median- 14 months Median- 18 months 5% 5% 5%/ 13%
37 3DCRT IMRT Protons Years treated Patients treated N=74 N=66 N=62 RT Dose 63 Gy ( ) 63 Gy (60-76) 74 Gy (63-81) % Stage III or higher 94% 95% 89% Median follow up 18 months 17 months 15 months GTV size 141 cm cm 3 68 cm 3 Grade 3+ esophagitis 18% 44% 5% Grade 3+ pneumonitis 30% 9% 2% Median overall survival 17.7 months 17.6 months 24.4 months
38 Multi-Institutional Research MD Anderson & MGH-- Phase II randomized study of IMRT vs Proton therapy for stage III NSCLC with concurrent chemotherapy Currently enrolling patients
39 RTOG 1308
40 Proton Collaborative Group (PCG)-Phase I/II Hypofractionation with concurrent chemotherapy Dose Dose/fx Fxs Weeks BED tbed 1 60 CGE CGE CGE CGE BED- biologic effective dose tbed-time dependent BED
41 Proton Collaborative Group (PCG)-Phase I/II Hypofractionation with concurrent chemotherapy Dose Dose/fx Fxs Weeks BED tbed 60 CGE CGE CGE CGE RTOG 0617 Dose Arms 60 Gy Gy BED- biologic effective dose tbed-time dependent BED
42 Treatment Planning
43 Uncertainties
44 Uncertainties with Protons
45
46
47 Uncertainties with Protons Do not treat with the most conformal plan Treat with the most conformal ROBUST plan that takes into consideration the uncertainties
48 A few of the uncertainties with Protons Range RBE Secondary neutron Distal fall off in low density lung
49 Protons: Range Uncertainty
50 Protons: Range Uncertainty
51 Protons: Range Uncertainty Add range uncertainty to the ITV target Avoid stopping a beam just proximal to the cord
52 RBE Uncertainties We use an RBE of 1.1 (understanding that it might be a bit higher at the distal end of the SOBP) Avoid stopping beams inside a major OAR Use multiple fields
53 Neutron dose Uncertainty Out of field neutron dose in double scatter proton therapy is similar to that of IMRT. Risk of 2 nd cancers from neutrons Patients with expected 10 year survival rates of <10%.
54 Distal Fall-off uncertainty Uncertain of the ability of protons to stop in low density lung Try to choose beam angles that stop in the mediastinum or chest wall rather than lung Use multiple fields
55 How to make a Robust Plan 4D CT simulation and draw igtv Treatment planning done on average scan with an over ride of the igtv with HU=50* Add 8-10 mm smearing Add range equation to the ITV Add block margin to PTV 3-4 beams Avoid beams that stop just proximal to an OAR Check target coverage on 0 and 50 phase of 4D Assess OAR dose without over rides
56 Daily Image Guidance Proton therapy requires accurate alignment Currently, using daily orthogonal kv imaging Stage I- fiducial markers (and bone) Stage II/III- bone alignment
57 Weekly Verification Scans Tumor changes Shrinking Growing Thoracic density changes or tumor displacement Pleural effusions Atelectasis
58 Verification Scans Evaluate coverage of the CTV and PTV Evaluate dose to critical structures (cord D0.1cc) Majority of the time don t replan Pull back the range due to tumor regression Completely replan for tumor displacement Problem for any type of RT
59 Re-evaluations (tumor regression) Simulation After 40 Gy
60 Re-evaluations (tumor regression) Old Plan
61 Re-evaluations (tumor regression) New Plan Old Plan
62 Re-evaluations- pleural effusion
63 Tumor displacement Simulation Scan After 1 week of treatment
64 Conclusions Particle therapy reduces the dose to OARs compared with IMRT, 3DCRT, SABR. Many patients this is clinically meaningful and allows for improvement in therapeutic ratio. Safer dose intensification Hypofractionation
65 Conclusions Treatment planning is challenging! But, several centers have successfully established lung cancer treatment with proton therapy and the clinical results have not demonstrated any unforeseen toxicities or problems with local control.
66 Thanks! Nancy Mendenhall RC Nichols Randy Henderson Zuofeng Li Soon Huh Stella Flampouri Debbie Louis Jeff Glidden Kevin Kirby Brian Harper Keri Hopper Lana Cook Abubakr Bajwa Harry D Agostino Dat Pham James Cury
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