Particle Therapy Cooperative Group North America Annual Conference

1. Particle Therapy Cooperative GroupNorth America Annual Conference Chicago, October 23-25, 2017

2. Excellent Acute Toxicity Outcomes with Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer: Initial Results of a Multi-institutional Phase II Trial J. Isabelle Choi, MD California Proton Therapy Center San Diego, California

3. Disclosures • Andrew L. Chang: • Proton Center Development Corporation • Hampton University Proton Therapy Institute • ProCure Oklahoma City Proton Therapy Center • ProCure Proton Therapy Center, Inc. • Varian Medical Systems • Sumitomo Heavy Industries • SAH Global Bahrain Proton Therapy Center • SAH Global Oman Proton Therapy Center • SAH Global Dubai Proton Therapy Center • VOA • Advanced Proton Therapy • Scripps San Diego Proton Therapy Center • Malaysian Proton Therapy Center

4. Background • Partial breast irradiation (PBI) with proton beam therapy (PBT) after lumpectomy for early stage breast cancer is an area of active investigation

5. Dosimetric Advantage of Proton Beam Therapy for PBI • PBT allows for superior sparing of normal breast tissue and other surrounding organs of interest (heart, lung)

6. Institutional Experiences • MGH (Gallan-Girodet S, et al., IJROBP 2014; Kozak KR, et al., IJROBP 2006) • Phase I, 19 pts treated with PBT (1-3 fields) and 79 pts treated with photons or mixed photons/electrons, 32 Gy in 8 fractions BID. • At 7 years f/u, 62% physician-reported good-excellent cosmesis, increased acute and late skin toxicity versus photon therapy. Excellent disease control (6% local failure). • National Cancer Center, Korea (Chang JH, et al., RadiotherOncol 2013) • Phase II, 30 patients treated with PBT (1-2 fields), 30 Gy in 5 fractions QD. • Median f/u 5 years. 69% physician-reported good-excellent cosmesis at 3 years - increased toxicity with single field plan. No local or distant failures. • Loma Linda University (Bush DA, et al., IJROBP 2014; Bush DA, et al., Clin Breast Ca 2011) • Phase II, 50 patients treated with PBT (2-4 fields), IDC ≤3 cm s/p lumpectomy, 40 Gy in 10 fractions QD. • Median f/u 48 months. 4 pts with grade 2 acute skin toxicity; 90% good-excellent cosmesis. No local failures.

7. Primary Aim • To investigate the feasibility, safety, and efficacy of delivering PBI with proton beam therapy in a multi-institutional setting

8. Proton Collaborative Group (PCG) BRE007-12 trial • Participating sites: • Hampton University Proton Therapy Institute (HUPTI) • ProCure PTC Oklahoma City • Northwestern Medicine Chicago Proton Center • Eligibility: • Age >50 years • ER+ • pN0 • IDC and/or DCIS ≤3 cm s/p lumpectomy with >2 mm margins • Excluded: • Prior RT, LCIS, ILC, multicentric disease

9. Radiation Therapy • Proton beam therapy (all uniform scanning except one patient treated with passive scatter) • 40 Gy / 4 Gy x 10 daily fractions • Minimum 3 fields used; minimum 2 fields treated daily • CTV = GTV + 1.5 cm radial margin • 3 mm retraction at skin and pec m.

10. Statistics and Accrual • Primary endpoint • Freedom from ipsilateral breast recurrence • Primary analysis • Null hypothesis: FFF of ipsilateral breast cancer recurrence is 85% or lower • Alternate hypothesis: FFF of ipsilateral breast cancer recurrence is 97% or higher • Powered to have a 95% probability of rejecting the null hypothesis • Planned sample size: 42 • Accrual • N = 42 from Feb 2013 to Nov 2016 • 40 patients initiated protocol treatment • Current analysis with data through Jun 2017

11. Study Endpoints • Secondary endpoints • Acute toxicity • Evaluated qweek with NCI CTCAE v4.0 toxicity grading scale • Patient-reported QOL • Breast Cancer Treatment Outcome Scale (BCTOS) at baseline prior to RT, and at 1 year and 3 years post-treatment • BTCOS scored 1-4 (1: none; 2: mild; 3: moderate; 4: large) • Physician-reported cosmesis assessment • Including photographs at pre-treatment baseline, and at 1 year and 3 years post-treatment • Correlation of DVH with ipsi breast volume on CT and bra cup size • Additional endpoints • Disease Control (ipsi second primary, regional recurrence, distant recurrence, RFS, OS, contralateral breast cancer, secondary primary cancer)

12. Results • Median follow-up: 17.8 months • (range 2-36 months)

13. Results: Disease Control • Primary endpoint • Freedom from ipsilateral breast cancer recurrence: 100% • Distant disease control: 100% • One patient developed a new hormone receptor-negative IDC of the contralateral breast

14. Results: Toxicity • Acute toxicity (CTCAE v4.0) • Grade 2: 6 events (1 - radiation dermatitis, 1 - lymphedema, 3 -hot flashes, 1 – fatigue) • Grade 3: 1 event (occurred 3 weeks after RT completion in the form of vascular disease requiring stent placement -- highly unlikely to be attributable to RT effects) • Patient-reported QOL (BTCOS) • Score of 4 assigned for change in nipple appearance (n=2), breast shape (n=2), and scar tissue formation (n=2) • Physician-reported assessment of overall breast cosmesis “good” or “excellent” for all patients

15. Conclusions • Proton PBI provides excellent early cancer control with acceptable cosmetic outcomes and minimal adverse effects as per patient- and physician-reported assessments • With continued follow-up, late toxicity and long term disease control outcomes will be assessed • Amendment in submission to IRB to increase enrollment to 138 patients

16. Acknowledgements • Proton Collaborative Group (PCG) • Protocol Chairs • Andrew L. Chang, MD – Study Chair • Carlos Vargas, MD – Co-Chair • Rashmi Benda, MD – Co-Chair • Wen Hsi, PhD - Physicist • Participating Sites • Hampton University Proton Therapy Institute (HUPTI) • ProCure PTC Oklahoma City • Northwestern Medicine Chicago Proton Center