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

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

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

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

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

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 monthsUNC 9603 I/II 62 24 moCALGB 30105 II 43 24 moNCCTG 0028 I 13 37 moRTOG 0117 I/II 44 (stage 3) 21.6 mo

Concurrent Chemotherapy: RTOG 0617

STRATIFY

RT Technique1. 3D-CRT2. IMRT

Zubrod3. 04. 1

PET Staging5. No6. Yes

Histology7. Squamous8. Non-

Squamous

RANDOMIZE

Concurrent Treatment Consolidation TreatmentArm AConcurrent chemotherapy*RT to 60 Gy, 5 x per wk for 6 wks

Arm AConsolidation chemotherapy*

Arm BConcurrent chemotherapy*RT to 74 Gy, 5 x per wk for 7.5 wks

Arm BConsolidation chemotherapy*

Arm CConcurrent chemotherapy* andCetuximabRT to 60 Gy, 5 x per wk for 6 wks

Arm CConsolidation chemotherapy* and Cetuximab

Arm DConcurrent chemotherapy* and CetuximabRT to 74 Gy, 5 x per wk for 7.5 wks

Arm DConsolidation chemotherapy* and Cetuximab

Bradley, ASCO 2013

RTOG 0617

Local Relapse also increased (37%) on 74 Gy armWell conducted trial allowing state of the art

technology and good QA

Bradley, ASCO 2013

Arm Median OS Severe Esophagitis

Grade 5 Toxicity

60 Gy 28.7 months 7% 2 patients

74 Gy 19.5 months 21% 10 patients

Conventional RT

Traditional “protracted” dose escalation is a flawed and failed strategy in combined modality therapy

Protracted Conventional Radiotherapy

Locally Advanced NSCLC

What Now?

• Alternate Radiotherapy Schedules

Hyperfractionation

• RTOG 9410: 1.2 Gy BID to 69.6 Gy

– Lower dose per fx reduced toxicity?

Curran, JNCI 2011

Con.STD 63Gy Con. HFX 69.6 GyMedian survival 17 mo 15.65-year survival 16% 13%Acute Esop. Tox. 22% 45%Late Pulm. Tox. 13% 19%

Hypofractionation

Trial RT Regimen Chemo Survival Late ToxicityEORTC(1999-03)

2.75 Gy x 24 (66 Gy)

Cisplatin 6 mg/m2 daily

3 yr: 33%

4 % Esophageal18 % Pulmonary

SOCCAR 2.75 Gy x 20 (55 Gy)

Cisplatin/vinorelbine

27.6 mo median

“acceptable” Stricture?

KROG(2003-05)

2.4 Gy x 25 (60 Gy)

Paclitaxel/carboplatin

28.1 momedian

2 hemoptysis3 stricture

• Higher dose per fraction – Safe with advanced technology?

Active Photon StudiesStage 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

What Else?• Charged particle therapy

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

Precise Energy Placement

16

17

Pediatric Malignancies• Reduced dose to normal tissue

- limit impact on growth- reduce secondary malignancy risk

Proton TherapyCost : $25,000,000 to > $200,000,000

Building Boom of Proton Beam Centers Flares Up in Washington and BaltimoreCancer 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 been reported

Early Lung Cancer

Photon SBRT

“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

Georg Radioth Onc 2008

• Reduced (low dose) lung , heart , esophagus dose with proton SBRT

Photon SBRT

RTOG 0236

• 60 Gy / 3 fx (peripheral tumors only)• 97% in-field local control

Timmerman JAMA 2010

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

Proton Therapy Locally Advanced Lung Cancer

Photon IMRT

Proton Therapy Locally Advanced Lung Cancer

V20 Lung = Volume of Lung Receiving 20 Gy

Proton Therapy Locally Advanced NSCLC

Chang et al Red Journal 2006

Stage III NSCLC

• Does what we see on paper (or the computer screen) translate into real life?

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

PT + ChemotherapyStage 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

PT + ChemotherapyStage 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

Locally Advanced• Primary 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

StratifyStage1.II2.IIIA3.IIIB

GTV1.<= 130 cc2.>130 cc

Histology1.Squamous2.Non-Squamous

NeoadjuvantChemotherapy1. Yes2. No

RANDO

MIZATIO

N

Photon: Highest achievable dose between 60-70 Gy at 2 Gy, once daily plus platinum-based doublet chemotherapy

Protons: Highest achievable dose between 60-70 Gy (RBE) at 2 Gy (RBE) once daily plus platinum-based doublet chemotherapy

Arms 1 and 2: Consolidation Chemotherapy x 2 is allowed

Arm 1

Arm 2

RTOG 1308: Phase III Randomized Trial Comparing Overall Survival after Photon vs. Proton Radiochemotherapy for Stage II-IIIB

NSCLC

Plan must meet dose and volume constraints of all OARs

Stage III Trials

• Ongoing and planned trials evaluating proton therapy

– Preoperative therapy

– Hypofractionated

– IMPT with simultaneous integrated boost

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