Good afternoon everyone, thank you for being here. My name is Katarina Petras, and I am a PGY4 radiation oncology resident at Northwestern. I’d like to thank the PTCOG scientific committee for inviting us to share our preliminary findings. Today I’ll be speaking on a multi-center experience of proton beam therapy in the treatment of H&N cancer. Multi-Center Experience of Proton Beam Therapy in the Treatment of H&N Cancer Chicago, October 24, 2017

Disclosures Katarina Petras, MD Michelle Gentile, MD, PhD None Michelle Gentile, MD, PhD John Chang, MD Dr. Gentile, Dr. Chang, and I have no disclosures.

Background Proton therapy is becoming a more widely available & applied treatment modality in H&N cancer The physical properties of protons make them aptly suited in the treatment of H&N cancer given improved conformality and superior dose distribution, potentially improving the therapeutic ratio As the incidence of cancers with expected excellent prognosis increases (ie: HPV+ OPX tumors), these patients are most at risk for late treatment-related toxicities Further investigation is needed into the safety and efficacy of proton therapy in H&N cancer Proton therapy is becoming a more widely available & applied treatment modality in H&N cancer. The physical properties of protons make them aptly suited in the treatment of H&N cancer given improved conformality and superior dose distribution, potentially improving the therapeutic ratio. As the incidence of cancers with expected excellent prognosis increases, such as in HPV+ oropharynx tumors, these patients are at a greater risk for late treatment- related toxicities. Further investigation is needed into the safety and efficacy of proton therapy in H&N cancer.

Study Design Prospectively collected clinical data from 8 different proton centers around the U.S. Northwestern, ProCure OKC, ProCure NJ, Willis-Knighton SCCA Proton Center, Scripps, Mayo AZ, Maryland Proton Center Proton Collaborative Group Registry Patients were treated for H&N cancer of adult histology in either the initial or retreatment setting RT delivered starting in 2010 – 2017 The data we present was prospectively collected from 8 different proton centers around the US. Patients were enrolled on a Proton Collaborative Group Registry and treated for H&N cancer of adult histology in either the initial or retreatment setting. Radiotherapy was delivered starting in 2010. Extra Data has been QA’d from Northwestern, Procure OKC, Procure NJ, and Mayo.

Study Design Started with a large data set of 512 patients (4/8 centers) After exclusions, 230 patients included in current analysis Most common exclusions (for current analysis) were: Data uncertainty (site, stage, dose) Histology (lymphoma, sarcoma, skin primary, or benign) IMRT only Palliative intent No follow-up data (required a minimum of 1 follow-up visit) In time for this analysis, we were able to QA data from 4 of the 8 centers (Northwestern, NJ, OKC, Mayo AZ). This gave us a large data set of 512 patients, and after preliminary exclusions, 230 patients were included. The most common reasons for exclusion were data uncertainty, certain histologies, use of IMRT only, palliative treatment intent, and absent follow-up data. We hope to QA the data further to clarify some of these issues & eventually include more patients from all 8 centers. Extra Data access (5), data uncertainty (35) Histology (23 – included benign histologies, lymphoma, sarcomas, or skin primary), incomplete staging (40), unclear primary tumor site (23) IMRT only (63) Palliative intent (23) No follow-up data (30) RT prescription not completed (3), unclear if ReRT (37)

Initial Course RT Patient Demographics Percent (%) Sex Male Female 99 57 63.5 36.5 Race White Asian African American Native American Unknown 129 14 8 3 2 82.7 9 5.1 1.9 1.3 Median Age 58 Range 8-91 Tobacco Use Former Never Current 63 82 11 40.4 52.6 7 I’d like to start by reviewing our group of 156 patients who underwent an initial course of treatment with proton beam therapy. The majority of these patients were male and Caucasian. The median patient age was 58, range 8-91. About one half of patients were never smokers, and 40% were former smokers. Unfortunately pack-year smoking data was not consistently recorded and is not available.

n=156 Percent (%) Tumor Site Salivary gland Sinus/nasal cavity Oropharynx Oral cavity Nasopharynx Larynx Hypopharynx Unknown primary 47 42 32 21 9 2 1 30.1 26.9 20.5 13.5 5.8 1.3 0.6 Histology Squamous cell carcinoma Adenoid cystic Mucoepidermoid Carcinoma NOS Esthesioneuroblastoma Unknown Other 65 20 17 11 8 14 41.7 12.8 10.9 7.0 5.1 9.0 The most common tumor sites included salivary gland, sinus, nasal cavity, and oropharynx. 20% of patients were of OPX primary, and almost 80% of these patients were confirmed to be HPV+. The most common histology was squamous cell carcinoma. Extra Other = acinic cell (4), adenocarcinoma (5), cystadenocarcinoma (2), mucosal melanoma (2), myoepithelial (1), neuroendocrine (4), papillary adenocarcinoma (1), small cell (1), SNUC (1) OPX patients (n=32): HPV+ (25), HPV- (3), unknown (4)

33% of proton only patients treated with PBS Percent (%) Stage (AJCC 7th edition) III IVA/B 30 73 19.2 46.8 Concurrent Chemo Yes No Unknown 58 97 2 37.1 62.1 12.8 Median dose Gy(RBE) Proton only (81%) Hybrid plan (19%) Proton boost 66.085 70.02 19.72 Range 54.12-79.06 Range 55.85-86.1 Range 5.45-54.05 66% of patients had advanced stage disease and 37% received concurrent chemotherapy. We found that were 2 plan types, proton only and hybrid proton/IMRT plans. About 80% of these patients were treated with a proton only plan. The median dose for proton only plans was 66 Gy. 33% of proton only patients were treated with PBS technique. The median dose for hybrid plans was 70 Gy with a median proton boost dose of about 20 Gy. Extras Median dose in proton only plans is lower than for hybrid plans. Practitioners may be decreasing their total dose to avoid toxicity associated with uncertainty in RBE. Post-op doses were standard range 60-66 with definitive doses closer to 70. 33% of proton only patients treated with PBS

Initial RT Course Acute & Late Grade 3+ Toxicities Grade 3 Toxicity Acute Incidence (n=156) Late Incidence (n=44) Fatigue 2 Anorexia 17 Hoarseness Skin pain 4 Dermatitis 15 1 Mucositis 24 Oral pain 14 Dysphagia 18 Esophagitis 16 Ear Pain Xerostomia 3 Nausea Total # patients 41 6 Acute toxicity data was available for all 156 patients, however only 28% of patients had enough follow-up to grade late toxicity. No acute or late grade 4 toxicities were identified. 41 patients, or 26%, experienced acute grade 3 toxicity. 6 patients experienced late grade 3 toxicity. One patient with late grade 3 anorexia had recorded PEG tube dependence.

ReRT Patient Demographics Percent (%) Sex Male Female 54 20 73 27 Race White Asian African American Unknown 60 7 5 2 81 9.5 6.8 2.7 Median Age Range 12-85 Tobacco Use Former Never Current 47 18 9 63.5 24.3 12.2 Now on to another group. 74 patients received H&N re-irradiation with proton beam therapy. Again the majority of these patients were male and Caucasian. The median age in this group was 60, range 12-85. About 60% of these patients were former smokers. Extra PY data not available

Squamous cell carcinoma Carcinoma NOS Adenocarcinoma Percent (%) Tumor Site Oropharynx Nasopharynx Oral cavity Sinus/nasal cavity Larynx Salivary gland Hypopharynx 26 15 11 7 5 3 35.1 20.3 14.9 9.5 6.8 4.1 Histology Squamous cell carcinoma Carcinoma NOS Adenocarcinoma Adenoid cystic carcinoma Mucoepidermoid Unknown Other 54 6 4 2 73.0 8.1 5.4 2.7 The most common tumor site in this group was oropharynx, 35%, and the most common overall histology was squamous cell carcinoma. About 38% of oropharynx patients were confirmed to be HPV+. Extra Other = neuroendocrine (1), pleomorphic carcinoma (1) OPX patients (n=26): HPV+ (10), HPV- (6), unknown (10)

30% of proton only patients treated with PBS Percent (%) Stage (AJCC 7th edition) III IVA/B 15 33 20.3 44.6 Concurrent Chemo Yes No Unknown 49 24 1 66.2 32.4 13.5 Median dose Gy(RBE) Proton only (95%) Hybrid plan (5%) Proton boost 68.04 30.13 Range 50.16-83.2 Range 60.04-73.02 Range 20.03-54.05 Again the majority of patients had advanced stage disease, and 66% received concurrent chemotherapy. 95% of patients were treated with protons only and the median plan dose was 66 Gy. 30% of these patients were treated with PBS technique. The remaining were treated with a hybrid plan and the median proton boost dose was 30 Gy. Extra Median dose in proton only plans is lower than for hybrid plans. Practitioners may be decreasing their total dose to avoid toxicity associated with uncertainty in RBE. Post-op doses were standard range 60-66 with definitive doses closer to 70. 30% of proton only patients treated with PBS

ReRT Acute & Late Grade 3+ Toxicities Grade 3 Toxicity Acute Incidence (n=74) Late Incidence (n=11) Anorexia 6 1 Hoarseness 3 Skin pain Dermatitis 5 Mucositis Oral pain 4 Dysphagia 7 Esophagitis 2 Ear pain Xerostomia Total # patients 21 All patients had acute toxicity data recorded but only 15% had enough follow-up to determine late toxicity. No acute or late grade 4 toxicities were identified. 21 patients, or 28%, had acute grade 3 toxicity. 2 patients had late grade 3 toxicity. Extra Other published ReRT data MacDonald: acute grade 3 toxicity in 13% of patients MSK: 25% with acute grade 3+ toxicity. 17% had late grade 3+ toxicity (92% of their patients had enough follow-up to grade late toxicity)

Analysis Now on to our statistical analysis.

Initial Course RT -All patients & plan types 1-year (%) 95% CI LC 97.8 91.5-99.5 DM 7.7 3.5-14 OS 95.2 88.7-98 PFS 86.3 77.8-91.8 DMFS 92.2 84.7-96.1 2-years (%) 95% CI 94.5 85.4-98 11.7 5.6-20.4 84.1 73-90.9 76.6 65.1-84.7 87.7 77-93.6 This first analysis included all initial course patients and plan types. We looked at the 1 and 2 year rates of LC, DM, OS, PFS, and DMFS. Despite being a heterogeneous group of patients, our outcomes are excellent with a median follow-up of 1 year. Although we would expect the majority of failures for H&N cancer to be in the first 2 years after treatment, ideally we would have at least 5 years of follow-up. However these results look encouraging given the limited follow-up period. Median follow-up 12 months (range 1-60)

Initial Course RT -Proton vs. Hybrid Plans 1-year (%) Proton Only Hybrid LC 97.3 100 DM 5.7 15.1 OS 97.5 86.4 PFS 90.4 71.2 DMFS 94.3 83.6 2-years (%) Proton Only Hybrid 94.6 93.8 11.1 15.1 84.5 81 79.1 65.7 88.4 83.6 p-value 0.83 0.32 0.92 0.23 0.25 Because so many proton centers are seeing referrals for hybrid plans where a proton boost is applied, we analyzed this outcome. When we compared these 1 and 2 year endpoints between proton only and hybrid plans, there were no statistically significant outcome differences. Again we would like to note that the median total dose was different between the 2 groups. 80% of these initial course RT patients were treated with a proton only plan. Among proton only plans, 33% were treated with PBS. Among hybrid plans, 17% were treated with PBS. Extra Median proton boost dose was about 20 Gy (range 5-54) (n=127) Proton only – 40% PBS, 37% scanning, 17% combo, 6% unknown. (n=29) Hybrid plans – 17% PBS, 52% scanning, 21% combo, 10% unknown. Unclear whether this is a difference in acute or late toxicity between proton only and hybrid plans. The median proton dose in hybrid plans was only about 20 Gy. This is not really enough to significantly reduce treatment related toxicity when it compromises a small portion of the total RT dose delivered. Median total dose: proton 66 Gy(RBE) and hybrid 70 Gy(RBE) Median proton boost dose: 20 Gy(RBE)

ReRT Course -All patients and plan types 1-year (%) 95% CI LC 69.7 48.7-83.5 DM 17.9 8.6-30 OS 57 41.1-70.1 PFS 36 22.4-49.7 DMFS 78.6 61.7-37 2-years (%) 95% CI 61 35.8-78.8 25.1 12.5-39.9 57 41.1-70.1 19.7 8.6-34.2 63 37-80.7 This analysis looks at our 74 patients who underwent a course of re-irradiation with proton beam therapy, and we calculated the same 1 and 2 year outcomes. Our results are relatively congruent with other published H&N re-irradiation data looking at similar outcomes, which I’ll outline on the following slide. Median follow-up 7 months (range 1-45)

ReRT Comparison Median f/u (mo) LC-1yr OS-1yr LC-2yr OS-2yr Acute G3+ Late G3+ MacDonald1 (n=61) 15 80% 60% 33% 15% 25% Romesser2 (n=92) 10 75% 65% ~50% ~45% <30% <20% Phan3 (n=60) 14 81% (LRC) 81% 73% (LRC) 69% 30% 20% Current study (n=74) 7 70% 57% 61% 28% 3%* This is a quick comparison of our findings to other published results of re-irradiation for H&N cancer. Our outcomes are similar to what has been reported by other institutions, particularly when looking at the 2 year mark. Small differences in outcomes may depend on a variety of heterogeneous histologies, sites, stages, etc. Acute and late toxicity was reported slightly differently in each individual study. Overall though, our numbers seem to be within close range of one another. Please remember that we had few patients with verified late toxicity. 1Emory and Indiana University 2MSK, ProCure NJ, Montefiore Medical Center, Northwestern 3MD Anderson, Mayo AZ, University of Cincinnati *only 15% of patients with enough follow-up to grade late toxicity

Oropharynx (Initial Course) -All plan types 1-year (%) 95% CI LC 100 -- OS 96.3 76.5-99.5 PFS 79.3 43.4-93.8 2-years (%) 95% CI 100 -- 96.3 76.5-99.5 79.3 43.4-93.8 We then wanted to look at the 28 oropharynx patients with known HPV status who underwent an initial course of proton beam therapy. 90% of these patients were HPV+ (25 of 28). 75% were treated with protons only and 25% with hybrid plans. As you can see, our 1 and 2 year outcomes are excellent. Extra LC, n=28, no events OS, n=28, 1 event PFS, n=28, 3 events Loma Linda Data (2005) – proton therapy for OPX cancer -29 patients -2 year DFS 81% -5 year LC 88%, LRC 84%, DFS 65% -Late grade 3 toxicity in 10% 75% proton only 25% hybrid plans

Oropharynx (Initial Course RT) HPV+ n=25 1-year (%) 95% CI LC 100 -- OS 95.8 73.9-99.4 PFS 83.9 43.2-96.4 2-years (%) 95% CI 100 -- 95.8 73.9-99.4 83.9 43.2-96.4 HPV- n=3 1-year(%) 95% CI LC 100 -- OS PFS NA 2-years (%) 95% CI 100 -- NA We did a comparison between HPV positive and negative patients. Of note, there were many more HPV+ patients. There were no statistically significant outcome differences based on HPV status. The 1 and 2-year rate of LC was 100% in both groups. The clinical outcomes of our HPV negative patients, though there were only 3 of them, are superior to prior historical reports where HPV negative patients have been found to do more poorly than similar patients with HPV positive disease. Although the 5 year outcomes may be more telling. Extra p-values: OS (0.72), LC (n/a, same values), 6-mo PFS (0.09) Given only 3 HPV- patients, there was not enough follow-up to compare 1 and 2-year PFS between the groups. 6-month PFS was 95.8% in HPV+ patients and 50% in HPV- patients We don’t have all the information for smoking PY RTOG 0129 2-year OS 87% (HPV+) vs 67% (HPV-), PFS 72% vs 51%. Both SS.

Study Limitations Heterogeneous patient population Limited long-term follow-up Clinical outcomes Late toxicity Different median dose between proton only and hybrid plans Logistical challenges of proton beam therapy? As with any study, there are limitations to our data. Firstly, we analyzed a heterogeneous patient population with mixed histologies, sites, and stages. Longer follow-up is needed to validate our findings, and ideally this would be at least 5 years. Many of our institutions function as large referral centers, and it can be difficult to have good long-term clinical follow-up as the majority of patients will follow with a physician closer to home. We should try to improve the collection of late toxicity data, as this is an important area of study in proton therapy. Additionally, there were different median doses between the proton only and hybrid plans. We hypothesize that practitioners may be decreasing their total proton doses to avoid toxicity associated with proton uncertainties. However, when looking at proton only vs hybrid plans among our initial course RT patients, there was no apparent difference in treatment efficacy. It would be interesting to know if there are differences in late toxicity between these 2 treatment approaches. Finally, we did not collect data regarding the logistical challenges of proton beam therapy such as the need for patient re-simulation as part of adaptive planning, which is one of the biggest challenges in treating H&N cancer with protons.

Conclusions Proton therapy provides good local control for initial course RT patients with H&N cancer (limited follow-up) It appears to be a safe and effective treatment modality in previously irradiated patients Our analysis showed minimal late grade 3 toxicity and no late grade 4 toxicity Future directions: Complete QA of large data set from multiple centers Verify as much high-grade late toxicity as possible In conclusion, proton therapy provides good local control for initial course RT patients with H&N cancers with this limited follow-up. It appears to be a safe and effective treatment modality in previously irradiated patients, and our results are congruent with reported outcomes from other institutions and collaborative groups. Our analysis showed minimal late grade 3 toxicity and no late grade 4 toxicity. Future directions of the project include completing a full QA of our large data set, collecting longer follow-up, and verifying as much high-grade late toxicity as possible.

THANK YOU! Dr. Michelle Gentile & Dr. John Chang Irene Helenowski, PhD All participating patients & their families All contributing proton centers & staff Dr. Carlos Vargas (PCG Study Chair) Dr. Gary Larson (OKC) Dr. William Hartsell (CHI) Dr. Henry Tsai (NJ) Dr. George Laramore (UW) Dr. Carl Rossi (Scripps) Dr. Lane Rosen (Willis-Knighton) Dr. Shahed Badiyan (Maryland) This project is part of a large collaborative effort to expand our knowledge of proton beam therapy and its potential benefits in the treatment of H&N cancer. I would like to thank my mentor Dr. Michelle Gentile and collaborator Dr. John Chang for their help in putting this project together. A big thanks to my statistician Irene Helenowski and to the patients and their families who participated in this registry. And last but not least, thank you to all the physicians and staff at our contributing centers.

QUESTIONS? Any questions? Sólheimajökull Glacier, Iceland