1. Jeffrey A. Bogart M.D. Upstate Medical University November 15, 2013
Proton Therapy for Lung Cancer Therapeutic Advance or The Straw that Broke the U.S. Medical System’s Back?
Jeffrey A. Bogart M.D.
Upstate Medical University
November 15, 2013

2. Disclosures Chair, Alliance Radiation Oncology Committee
Stipend
Upstate Medical University recently signed a MOU with Advanced Oncotherapy PLC to proceed with developing a proton therapy center

3. Learning Objectives
Review current state of the art (radio)therapy for locally advanced NSCLC
Describe available evidence for proton therapy in treatment of early stage NSCLC
Discuss opportunities and challenges in treatment of locally advanced NSCLC with proton therapy

4. Background Stage III NSCLC Primary RT: Local tumor control ~ 15%
ChemoRT: In-field failure 33%+ (RTOG 9410)
Hypothesis: Modulating RT delivery will improve local control and ultimately survival

5. RT Practice Standards The new millennium …
IMRT, IGRT, 4D planning now routine
Should shift therapeutic index
But ..no change in the radiotherapy dose schedule for locally advanced NSCLC since the 1970’s
6000 cGy / 6 weeks

6. 3D Dose Escalation Dose Escalation : Conventional Fractionation
74 Gy in 2 Gy fractions was feasible with concurrent weekly paclitaxel and carboplatin
Trial
Phase n
Med survival
RTOG 9410 (63Gy)
III
200
17 months
UNC 9603
I/II 62
24 mo
CALGB 30105 II 43
NCCTG 0028 I 13
37 mo
RTOG 0117
44 (stage 3)
21.6 mo

7. Concurrent Chemotherapy: RTOG 0617
STRATIFY
RT Technique
3D-CRT
IMRT
Zubrod 1
PET Staging No
Yes
Histology
Squamous
Non-Squamous
RANDOMIZE
Concurrent Treatment
Consolidation Treatment
Arm A
Concurrent chemotherapy*
RT to 60 Gy, 5 x per wk for 6 wks
Consolidation chemotherapy*
Arm B
RT to 74 Gy, 5 x per wk for 7.5 wks
Arm C
Concurrent chemotherapy* and
Cetuximab
Consolidation chemotherapy* and Cetuximab
Arm D
Concurrent chemotherapy* and Cetuximab
Bradley, ASCO 2013

8. Well conducted trial allowing state of the art technology and good QA
RTOG 0617
Local Relapse also increased (37%) on 74 Gy arm
Well conducted trial allowing state of the art technology and good QA
Arm
Median OS
Severe Esophagitis
Grade 5 Toxicity
60 Gy
28.7 months 7%
2 patients
74 Gy
19.5 months
21%
10 patients
Bradley, ASCO 2013

9. Locally Advanced NSCLC Conventional Radiotherapy
Conventional RT
Traditional “protracted” dose escalation is a flawed and failed strategy in combined modality therapy
Locally Advanced NSCLC
Protracted
Conventional Radiotherapy

10. What Now?
Alternate Radiotherapy Schedules

11. Hyperfractionation RTOG 9410: 1.2 Gy BID to 69.6 Gy
Lower dose per fx  reduced toxicity?
Con.STD 63Gy
Con. HFX Gy
Median survival
17 mo
15.6
5-year survival
16%
13%
Acute Esop. Tox.
22%
45%
Late Pulm. Tox.
19%
Curran, JNCI 2011 11

12. Higher dose per fraction
Hypofractionation
Higher dose per fraction
Safe with advanced technology?
Trial
RT Regimen
Chemo
Survival
Late Toxicity
EORTC
( )
2.75 Gy x 24 (66 Gy)
Cisplatin
6 mg/m2 daily
3 yr: 33%
4 % Esophageal
18 % Pulmonary
SOCCAR
2.75 Gy x 20 (55 Gy)
Cisplatin/
vinorelbine
27.6 mo median
“acceptable”
Stricture?
KROG
( )
2.4 Gy x 25 (60 Gy)
Paclitaxel/
carboplatin
28.1 mo
median
2 hemoptysis
3 stricture 12

13. Active Photon Studies Stage III ChemoRT
CALGB 31102
Phase I : Maintain Total Dose at 60Gy
Increase dose/fraction - reduce treatment time
Next cohort : 3 Gy x 20 Fx over 4 weeks
RTOG 1106
Random phase II : individualized adaptive RT using during-treatment FDG-PET/CT
Doses as high as 85 Gy in 30 fx given 13

14. What Else?
Charged particle therapy

15. Proton Therapy + Charged Particle
Physical properties differ from photons
Potential for better protection of normal structures
But treatment planning relatively immature c/w photons
Passive Scattering (~ 3D) : majority of published studies
IMPT (~ IMRT) – dose painting
Biologic efficacy similar

16. Precise energy placement

17. Pediatric Malignancies
Reduced dose to normal tissue
limit impact on growth
reduce secondary malignancy risk

18. Proton Therapy
Cost : $25,000,000 to > $200,000,000

20. Building Boom of Proton Beam Centers Flares Up in Washington and Baltimore
Cancer Letter : Oct 25, 2013
“About 100,000 people have been treated with proton beam radiation, and about 85 percent of them received it for prostate cancer “
- Level 1 evidence supporting protons over photons does not exist
Undue severe toxicity has not ben reported

22. Early Lung Cancer

23. Photon SBRT

24. “Protons generate larger high-dose regions than photons because of range uncertainties. This can result in nearby healthy organs (e.g., chest wall) receiving close to the prescription dose, at least when two to three beams are used, such as in our study”
Seco et al Red Journal 2012

25. reduced (low dose) lung , heart , esophagus dose with proton SBRT
Georg Radioth Onc 2008

26. Photon SBRT RTOG 0236 60 Gy / 3 fx (peripheral tumors only)
97% in-field local control
Timmerman JAMA 2010

27. Proton Therapy Early lung Cancer
Loma Linda (2013)
111 patients, T1+ T2 tumors
4-year OS dose dependent :18% (50 Gy), 32% (60 Gy), 51%(70 Gy)
Local Control 96% for Peripheral T1 if 60 Gy +
Clinical radiation pneumonitis was not found to be a significant complication.
“Meta-analysis” (2010)
“Five-year overall survival similar with SBRT (42%), proton therapy (40%) and carbon-iontherapy (42%). However, caution is warranted due to the limited number of patients and limited length of follow-up of the particle studies”
Bush et al Red Journal 2013
Grutters et al Radioth Oncol 2010

28. Proton Therapy Locally Advanced Lung Cancer
Photon IMRT

29. Proton Therapy Locally Advanced Lung Cancer
V20 Lung = Volume of Lung Receiving 20 Gy

30. Proton Therapy Locally Advanced NSCLC
Reduced low dose exposure to lungs and medium / low dose to heart V20, V 5……TOG 0617
Chang et al Red Journal 2006

31. Stage III NSCLC
Does what we see on paper (or the computer screen) translate into real life?

32. Proton Therapy Locally Advanced Lung Cancer
Complicating Factors
Depth of penetration /Bragg peak varies significantly based on the density of tissues
Range uncertainty (extra margin of safety)
Tumor Motion introduces further uncertainty

33. PT + Chemotherapy Stage III NSCLC
Phase II (MD Anderson, n = 44)
74 Gy(RBE) + weekly carboplatin (AUC 2) and paclitaxel (50 mg/m2 )
FDG-PET/CT staged
passively scattered proton
Cone beam CT not available
Median Survival 29.4 months (19.7 month median FU)
Local relapse 20.5 % , 9.3 % nodal relapse
Toxicity
11.4% grade 3 dermatitis , 11.4% grade 3 esophagitis
1 grade 3 pneumonitis and 1 pulmonary/pleural fistula
Chang et al Cancer 2011

34. PT + Chemotherapy Stage III NSCLC
University of Florida (n = 19)
Median 74 Gy(RBE) + chemotherapy
Median 16 month FU
Toxicity
1 acute grade 3 and 1 late grade 3 non-hematologic toxicity
1 documented in-field progression
Hoppe et al Lung Cancer 2012

35. Locally Advanced Primary RT Re-irradiation(n= 33) PORT/Mediastinal RT
Poor DFS/OS with PT alone
Re-irradiation(n= 33)
MD Anderson
Repeat RT to 66 Gy (median 3 year interval)
54% 1-yr local control, 9/33 in-field relapse
Toxicity
Gr 3 : 9% Esophageal, 21 % pulmonary
Gr 4 : 3% Esophageal, 7 % pulmonary
PORT/Mediastinal RT
Better Protect Heart and Surrounding Lung c/w photon
McAvoy et al Radiother Oncol 2013

36. RTOG 1308: Phase III Randomized Trial Comparing Overall Survival after Photon vs Proton Radiochemotherapy for Stage II-IIIB NSCLC
Stratify
Stage
1.II
2.IIIA
3.IIIB
GTV
1.<= 130 cc
2.>130 cc
Histology
1.Squamous
2.Non-Squamous
Neoadjuvant
Chemotherapy
Yes No
RANDOMIZATION
Arm 1
Photon: Highest achievable dose between Gy at 2 Gy, once daily plus platinum-based doublet chemotherapy
Arms 1 and 2: Consolidation Chemotherapy x 2 is allowed
Arm 2
Protons: Highest achievable dose between Gy (RBE) at 2 Gy (RBE) once daily plus platinum-based doublet chemotherapy
Plan must meet dose and volume constraints of all OARs

37. Stage III Trials Ongoing and planned trials evaluating proton therapy
Preoperative therapy
Hypofractionated
IMPT with simultaneous integrated boost

38. Conclusions RTOG 0617 set the bar high : 28 month median OS
Modern staging (FDG-PET)
Sophisticated Treatment Planning
Whether altering fractionation, dose , or treatment particle will improve outcomes is unclear
Proton therapy has potential to permit less toxic delivery of intensive RT … but limited data
Treatment techniques rapidly evolving (IMPT/CBCT)
PT may facilitate getting to the the right RT schedule