The theme for this year's conference was New Frontiers in Particle Therapy. Objectives for the 6th annual conference were to: Maintain best practices for proton therapy patient selection by recognizing maximum opportunity for toxicity reduction and/or tumor control probability improvement; appropriately identify patients for clinical trials and employ resources to overcome barriers to improve enrollment; determine where and when to implement advanced treatment planning approaches such as Monte Carlo, relative biological effectiveness (RBE), and linear energy transfer (LET); and consider limitations of proton therapy and recognize when applications of dual modality or non-proton therapy options are indicated to achieve optimal patient outcomes.Healthcare professionals who treat cancer patients using radiation therapy/particle therapy and specifically:BACKGROUND: Differences in proton and photon physics is an underlying reason for differences in biological effectiveness. Photons set in motion delta-electrons, which transfer energy to biological targets. According to Bethe-Bloch formula, an electron has the same LET as a proton travelling with the same velocity. This suggests that differences in energy spectra of electrons and protons are crucial for understanding differences in biological effectiveness. Electron spectra are complex and the term itself is prone to misinterpretation. We define the spectrum unambiguously as the probability distribution of energy of electrons entering a microscopic biological target.METHODS AND MATERIALS: We account only for electrons that reach the target volume. In previous studies, average LETs were calculated using the source spectra, i.e. distributions of initial electron energies at the point of origin. These are not the spectra of electrons reaching the target. Electrons are mostly produced outside the target and lose some energy before they reach it. Using source spectra overestimates RBE variation with beam energy, NCRP 181. We calculate spectra of electrons entering microscopic volumes by solving an electron transport equation with Monte Carlo.RESULTS: We report dose- and frequency averaged LETs for x-ray, brachytherapy, and gamma sources. For a 60Co source, our LETD is 4.6 keV/μm, an order of magnitude higher than reported previously, and higher than LET of protons with energies >10 MeV. The latter implies proton RBE<1 at higher energies. Our model (Vassiliev et al. Phys. Med. Biol. 2018) resolves this problem. It substantiates the use of LETF, which in our calculations is 0.40 keV/μm for 60Co.CONCLUSIONS: We propose a definition of delta electron spectrum for radiobiological modelling and an algorithm for calculating it. We report average LETs for several sources. Our results are very different from those previously reported. They support using LETF instead of LETD.BACKGROUND: Hypofractionated proton therapy with passive techniques for hepatocellular carcinoma (HCC) may have limitations when tumors are adjacent to organs-at-risk (OARs), which may result in tumor underdosage and lead to inferior local control. We present the first series of HCC patients treated with pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) using a simultaneous-integrated boost and protection (SIB/SIP) technique to escalate tumor dose while protecting adjacent OARs.METHODS AND MATERIALS: Sixteen consecutive HCC patients were treated between 2015–2018 with a 15-fraction regimen using IMPT SIB/SIP. SIB/SIP dose levels generally ranged from 37.5 to 67.5 GyRBE to minimize dose to OARs at their respective dose-limiting thresholds (e.g. luminal gastrointestinal organs, chest wall). Hepatotoxicity was defined by a Child-Pugh (CP) score increase of 2 or greater and/or any RTOG grade 3 enzyme elevation. Other toxicities were graded by CTCAEv5.0. Overall survival and local-progression-free survival were calculated using the Kaplan-Meier method.RESULTS: Patients most commonly had BCLC stage C (50%) and CP-A cirrhosis (71%). Median gross tumor volume (GTV) size was 12.7cm (599cc [228–1617]), and 38% had gross vascular invasion. Median GTV dosimetric parameters included: maximum prescription dose 67.5 GyRBE (60–67.5), mean 62.5 GyRBE (54.0–69.5), D1 68.0 GyRBE (61.6–71.3), and D99 50.4 GyRBE (33.4–67.7). Median liver-GTV parameters included: volume 1403.4cc (805–2130), mean 14.6 GyRBE (11.1–19.6), V30GyRBE of 27% (12%–35%), and V20GyRBE of 32% (21%–47%). At a median follow-up of 447 days (164–894) in alive patients, the median survival and 1-year overall survival was 22 months and 60%, respectively. Local control was 88% with no isolated local failures. Three patients experienced hepatotoxicity with no RILD-related deaths. No acute or late GI grade ≥2 occurred. One patient developed grade 3 chest wall toxicity.CONCLUSION: In our series of HCC patients with large tumors near OARs, IMPT SIB/SIP results in excellent local control and acceptable toxicities.BACKGROUND: While hypofractionated (Hypo) radiotherapy (RT) has widely replaced standard fractionated RT in the treatment of early-stage non-small cell lung cancer (NSCLC), major side effects have limited its use in advanced NSCLC. Based on the improved dosimetry of proton therapy (PT), we investigated the HypoPT approach for stage II–III NSCLC.METHODS AND MATERIALS: Between March 2013 and November 2018, 28 patients from 4 centers were enrolled on a clinical trial of HypoPT with concurrent chemotherapy followed by adjuvant systemic therapy. Patients could be simultaneously enrolled in a phase 1 study and receive doses of 2.5 (n=14), 3 (n=6), 3.53(n=7), and 4 Gy/fraction (n=1) to a total dose of 60 GyRBE according to the open arm and organ-at-risk (OAR) dosimetric constraints. Patients had stage IIA (n=3), IIB (n=3), IIIA (n=15), and IIIB (n=7) NSCLC. CTCAE, v4.0, was used for toxicity assessment. The primary endpoint of the study was 1-year overall survival (OS). The study closed prematurely due to slow accrual.RESULTS: The median follow-up for surviving patients was 23 months (range, 1–60). The 1- and 2-year OS rates were 89% and 66%, and the 1- and 2-year progression-free survival rates were 70% and 60%, respectively. Three patients died within 3 months of completing HypoPT: 1 from a bronchial hemorrhage; 1 from congestive heart failure following infectious pneumonia and C. Diff colitis; and 1 from paraneoplastic SIADH after completing just 42 Gy at 3.53 Gy/fraction. Additionally, 6 patients died more than 1 year after HypoPT: 5 from disease progression and 1 from a cardiac event.CONCLUSIONS: In this phase I/II study, HypoPT at 2.5 to 3.53 Gy per fraction to a total 60 Gy (RBE) with concurrent chemotherapy was well tolerated with favorable PFS and OS. A large randomized clinical trial comparing HypoPT with standard fractionated RT or PT is warranted, especially in the setting of consolidation immunotherapy.BACKGROUND: Re-irradiation (Re-RT) for rectal cancer (RC) in patients with prior pelvic RT has been shown to be safe and effective. However, limited data exists with the use of proton therapy (PT). We hypothesize that PT is a safe and feasible for re-treatment and may allow for decrease in toxicity or treatment escalation.METHODS AND MATERIALS: We performed a single institutional retrospective IRB-approved analysis of all RC patients with any prior pelvic RT re-irradiated with Pencil-Beam Scanning proton therapy (PBSPT). We collected patient and treatment characteristics including prior diagnosis and treatment; RC diagnosis and re-irradiation records; and toxicities. Outcomes, including overall Survival (OS) and Local Control (LC), were estimated using Kaplan-Meier.RESULTS: Twenty-six patients (median follow-up 15.3 months) received proton PBSPT Re-RT from 2016–2018: 16 patients w/ recurrent RC [median prior dose 52.2 Gy (43.2–63.0)] and 10 patients w/ de novo RC and variable prior RT (9 for prostate, 1 for ovarian). Median Re-RT dose was 44.4 Gy [(16.0–60.0); 20/26 BID], and 22 received concurrent chemotherapy. Five underwent surgical resection (all R0). Three patients experienced grade 3 acute toxicities, and no acute Grade 4–5 toxicities were observed. Two patients had grade 3+ late toxicities, including a grade 5 toxicity occurring in a patient with history of significant injury from prior RT. One-year LC and OS were 76.5% (95% CI 66.0–86.9%) and 77.7% (95% CI 68.8–86.6%), respectively.CONCLUSION: In this largest such series, early results of PT for Re-RT for RC are promising, with longer follow-up needed.BACKGROUND: Recent trends including proton therapy and reduced-dose cyclophosphamide have been adapted in head and neck rhabdomyosarcoma (HN-RMS) to reduce late morbidity. Our primary goal was to analyze local control and survival outcomes after photon versus proton irradiation in pediatric patients with HN-RMS, with the secondary goal of analyzing the effect of cyclophosphamide dose on disease outcomes.METHODS AND MATERIALS: This was a cohort study comprising 76 pediatric patients treated with definitive chemoradiation for HN-RMS from 2000 to 2018. Fifty-one patients (67%) were treated with intensity-modulated photon radiation therapy (IMRT) and 25 patients (33%) were treated with proton therapy.RESULTS: Local failure (LF) at 3 years was 21.8% for parameningeal RMS and 0% for orbital RMS and other head and neck sites (p=0.24). Patients who were treated with protons were more likely to have received reduced dose cyclophosphamide (p<0.0001). The 3-year LF was 10.0% in the IMRT cohort versus 21.6% in the proton cohort (p=0.07). Cyclophosphamide dose was associated with LF: the 3-year LF was 3.9% for patients who received a cumulative dose of >20g/m2 versus 18.4% for ≤20g/m2 (p=0.04). Among patients with parameningeal RMS (n=59), both the cumulative cyclophosphamide dose and dose-intensity were associated with local failure (p=0.01). There were no differences in survival outcomes among the IMRT and proton cohorts. There was a trend toward worse event-free survival in patients with parameningeal RMS who received reduced dose-intensity cyclophosphamide (46.1% versus 67.5%, p=0.11).CONCLUSIONS: Longer follow-up is needed in the proton cohort, although it appears that the dose of cyclophosphamide, rather than radiation modality, is likely the factor affecting local disease control. Efforts focused on further evaluating the optimal dose of cyclophosphamide or alkylating agents needed to balance disease control with toxicity are needed.BACKGROUND: Due to the excellent outcomes with image-guided stereotactic body radiotherapy (SBRT) for patients with early-stage non-small cell lung cancer (NSCLC), and the low treatment-related toxicities using proton therapy, we investigated treatment outcomes and toxicities for delivering hypofractionated proton therapy (PT).METHODS AND MATERIALS: Between 2009 and 2018, 22 patients with T1–T2N0M0 NSCLC (45% T1, 55% T2) were enrolled and treated with image-guided hypofractionated PT on an IRB-approved phase II clinical trial. The median age at diagnosis was 72 years (range, 58 – 90). Patients underwent 4-dimensional computed tomography (CT) simulation following fiducial marker placement, and daily image guidance was performed. Nine patients (41%) were treated with 48 GyRBE in 4 fractions for peripheral lesions, and 13 patients (59%) were treated with 60 GyRBE in 10 fractions for central lesions. Patients were assessed for CTCAEv4 toxicities weekly during treatment, and at regular follow-up intervals with CT imaging for tumor assessment. Overall survival, cause-specific survival, local control, regional control, and metastases-free survival were evaluated using cumulative incidence with competing risks.RESULTS: The median follow-up for all patients was 3.5 years (range, 0.2–8.8 years). The overall survival rates at 3 and 5 years were 81% and 49%, respectively. The cause-specific survival rates at 3 and 5 years were 100% and 75%, respectively. The 3-year local, regional, and distant control rates were 86%, 85%, and 95%, respectively. Four patients experienced in-field recurrences. The median time to local recurrence was 26.5 months (range, 19–47 months). One patient (5%) developed a late grade 3 bronchial stricture that required hospitalization and stent.CONCLUSIONS: Image-guided hypofractionated PT for early-stage NSCLC provides promising local control and long-term survival with low toxicities. Regional nodal and distant relapses remain a problem.BACKGROUND: To report clinical outcomes associated with post-prostatectomy PT. Toxicity outcomes for this cohort were recently published.METHODS AND MATERIALS: The first 100 consecutive patients from 2010–2016 were retrospectively assessed. Biochemical failure (BF; 2 consecutive rises above the nadir), first site of clinical failure – local, regional, and/or distant metastasis (DM) – and overall survival were recorded from start of radiation. BF- and DM-free survival Kaplan-Meier curves were estimated. Cox proportion hazards model was used to assess uni- (UVA) and multivariable association (MVA) with BF; variables with <0.1 were included in the multivariable model.RESULTS: Median age and months after surgery were respectively 64 years (range 42–77) and 25 (5–216). PT received was 70.2Gy (RBE) (89%), salvage (93%), prostate bed-only (80%), pencil beam scanning (86%), with intensity-modulated radiation therapy (31%), and with androgen deprivation (34%). Median follow-up was 55mo (16–80). BF was noted in 39 patients (39%). Median time to BF was 23mo (5–69). For patients with BF, local failure was eventually noted in 1 (1%) patient at 30mo. Regional pelvic nodal failure was noted in 4 patients (4%) – all treated to the prostate bed-only – at median 32mo (10–38), 2 of whom also had DM. DM occurred in 6 patients (6%) at median 30mo (10–41), 5 with bony and 1 with lung involvement. There was 1 death at 24mo, unrelated to prostate cancer. In summary, 4.5 yr BF free-, DM free-, and overall-survival were 61%, 94%, and 99%, respectively, in this single institution cohort treated primarily to the prostate bed only without androgen deprivation. On MVA, Gleason >7 (HR 3.55, 95% CI 1.83–6.88, p=0.000) and whole-pelvis with prostate bed PT (HR 0.28, 95% CI 0.10–0.79, p<0.016) were associated with BF.CONCLUSIONS: Post-prostatectomy PT is feasible with comparable clinical outcomes to historical photon outcomes.BACKGROUND: For most disease sites, level 1 evidence is lacking for proton beam therapy (PBT). By identifying target populations that would benefit most from PBT, prospective registries could overcome the challenges in clinical trials enrollment. Herein, we report clinical outcomes of patients treated with PBT for locally advanced non-small cell lung cancer (LA-NSCLC).METHODS AND MATERIALS: Data were obtained from the multi-institutional prospective database of the Proton Collaborative Group (PCG). Inclusion criteria of our study were stage III LA-NSCLC, use of PBT, and availability of follow-up data. Survival time was calculated from the start of treatment until death or last follow-up. Kaplan-Meier curves were generated for groups of interest and compared with log-rank tests. Cox regression modeling was used to evaluate the relationship between selected covariates and overall survival (OS).RESULTS: A total of 195 patients were included in the analysis. PBT alone was given to 93% of patients with a median equivalent dose in 2 Gy fractions (EQD2) of 63.8 Gy(RBE). Pencil beam scanning (PBS) was used in 20% of treatments. Treatment-related grade 3 adverse events (AEs) were rare: one pneumonitis, two dermatitis, and three esophagitis. No grade 4 events were reported. Two grade 5 events occurred, both cardiological, probably unrelated to PBT. The median follow-up time for living patients was 13.6 months and the median OS was 19.0 months. On multivariate analysis, good performance status (HR=0.26, 95% CI 0.15–0.47, p<0.0001), PBS use (HR=0.45, 95% CI 0.20–0.99, p=0.046), and increased EQD2 (HR=0.97, 95% CI 0.96–0.98, p<0.0001) were associated with decreased mortality.CONCLUSION: PBT appears to yield low rates of AEs with encouraging OS for the treatment of LA-NSCLC. PBS use and increased EQD2 can potentially increase OS. Prospective databases such as the PCG registry could play a key role in the future but need meticulous updates to reflect the clinical reality.PURPOSE: To evaluate treatment outcomes following definitive or adjuvant high-dose, image-guided proton therapy for patients with skull-base chordoma.METHODS AND MATERIALS: Between February 2007 and February 2018, 91 patients with a median age of 53 years (range, 22–78 years) with a skull-base chordoma were treated with passively scattered 3D-conformal proton therapy to a median dose of 73.8 Gy(RBE) (range, 69.6–75.6 GyRBE) on a prospectively collected, IRB-approved outcomes tracking protocol.RESULTS: The median age was 53 years (range, 22–78 years). Two patients received a component of intensity-modulated radiotherapy. Seventy percent (n=64) were men and 30% (n=27) were woman. Eighty-two percent (n=75) of patients had macroscopic disease at the time of radiotherapy; 18% (n=16) had undergone a macroscopic gross total resection. Overall survival, cause-specific survival, local control, and RT-related grade 3 toxicity-free survival were calculated. Proton therapy-related toxicities were scored using CTCAE v4.0. With a median follow-up of 3.7 years (range, 0.2–10 years), 26 patients experienced disease recurrence, including 26 local, 0 regional, and 1 distant recurrence. The median time to local progression was 2.2 years (range, 0.4–7.0 years). At the time of last follow-up, 66 patients were alive (56 with no evidence of disease progression) and 25 were deceased (18 with disease progression). There were no acute grade 3 toxicities related to the radiation therapy. The 4-year actuarial rates of overall survival, cause-specific survival, local control, and radiation therapy-related grade 3 toxicity-free survival were 83%, 87%, 76% and 83%, respectively.CONCLUSION: Definitive or adjuvant high-dose passively scattered 3-dimensional conformal proton therapy for skull-base chordoma provides acceptable local control, comparing favorably to historic photon data, with no acute grade ≥3 radiation-related toxicity and an acceptable rate of grade ≥3 late toxicity. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities.BACKGROUND: Post-prostatectomy radiation improves disease control, but limited data exist regarding outcomes, toxicities, and patient-reported quality-of-life with proton therapy.METHODS AND MATERIALS: The first 101 consecutive patients treated with double-scattered proton therapy (DSPT) between 2006 and 2015 were retrospectively reviewed. Seventy-eight patients received DSPT to the prostate bed only. Twenty-three received a DSPT prostate-bed boost following prostate-bed and pelvic-node treatment (3 with conformal 3-dimensional radiotherapy; 20 with intensity-modulated radiotherapy). Ten adjuvant patients received a median dose of 66.6 GyRBE (range, 66.0–70.2). Ninety-one salvage patients received a median dose of 70.2 GyRBE (range, 66.0–78.0). Three patients had a single positive lymph node. Forty-seven patients received androgen deprivation therapy (ADT) for a median of 9 months (range, 1–30). Toxicities (CTCAE, v4.0) were prospectively graded, and patient-reported quality of life data were reviewed.RESULTS: The median follow-up was 5.0 years (range, 0.8–11.3). Five-year biochemical relapse-free and distant metastases-free survival rates were 69% and 90% for adjuvant patients, 58% and 96% for salvage patients, and 58% and 95% overall. ADT was associated with improvement in biochemical relapse-free survival on univariate analysis (p=0.0286). Acute and late >grade 3 genitourinary toxicity rates were 1% and 6%. No patients had >grade 3 gastrointestinal toxicity. Acute and late grade 2 gastrointestinal toxicities were 5% and 2%. The median and range International Prostate Symptom Score, International Index of Erectile Function, and Expanded Prostate Cancer Index Composite bowel function and bother were 5 (range, 0–33), 7 (range, 2–25), and 100 (range, 42–100), 92 (range, 57–100), respectively at baseline, and 11 (range, 0–34), 5 (range, 4–24), 92 (range, 17–100) and 89 (range, 42–100) at the 5-year follow-up.CONCLUSION: High-dose post-prostatectomy PT provides effective long-term biochemical control and freedom from metastasis, with low acute and long-term gastrointestinal and genitourinary toxicity.BACKGROUND: Patients with esophageal or gastroesophageal junction (GEJ) cancers with isolated locoregional recurrences have limited definitive treatment options. Reirradiation with modest photon doses is associated with high toxicity rates. Proton therapy improves normal tissue sparing and may more safely allow reirradiation dose escalation. Outcomes and toxicities from the Proton Collaborative Group registry assessing proton reirradiation for esophageal/GEJ cancer locoregional recurrences are reported.METHODS AND MATERIALS: This IRB-approved prospective, multi-institutional registry was queried for recurrent esophageal/GEJ cancer treated with a second course of radiotherapy using protons. Baseline demographics, treatment details, outcomes, and toxicities (CTCAEv4.0) were evaluated.RESULTS: Twenty-five consecutive patients retreated from 7/2012–4/2018 were analyzed. Patients were a median of 70 years (52–82) and predominantly male (88%) and non-Hispanic Caucasian (88%) with adenocarcinoma (68%). Initial stage was: T1–4%, T2–8%, T3–76%, unknown–8%; N0–24%, N1–48%, N2–20%, unknown–8%; stage I–4%, IIA–4%, IIB–24%, IIIA–40%, IIIB–16%, IV–4%, unknown–4%. During their initial treatment (median 50.4/1.8Gy), all received concurrent chemotherapy, and five patients (20%) underwent resection. Median time to recurrence was 14.0 months (4.1–134.0). Proton reirradiation was delivered using uniform scanning or passive scattering (n=21) or pencil beam scanning (n=4) to a median 45.9Gy(RBE) (30.1–60.5) in 12–42 fractions. Eleven patients (44%) received concurrent chemotherapy. Median follow-up from reirradiation completion was 23.1 months among living patients. Fifteen patients died; 6/18-month survivals were 48%/24%. Only two patients (8%) developed locoregional recurrences (9.2 and 11.1 months following reirradiation) both salvaged with surgical resection. Grade 3 toxicities occurred in 20% (anemia=1; anorexia=2; dysphagia=2; esophagitis=2) and grade 2 in 44% (most commonly, fatigue=6). Grade ≥2 esophagitis and pneumonitis occurred in 16% and 0%, respectively. No esophageal fistula/stricture/necrosis and no grade 4–5 events occurred.CONCLUSION: Proton reirradiation for locoregionally recurrent esophageal/GEJ cancers is feasible, achieves durable local control, and has relatively limited toxicity. Additional prospective investigations and analyses of cumulative dose constraints are warranted.BACKGROUND: Proton partial breast irradiation (PBI) may decrease morbidity versus photon PBI by allowing superior normal tissue sparing. Single-institutional studies have reported feasibility of proton PBI but with conflicting toxicity results. We report 3-year outcomes of a prospective phase II trial investigating efficacy and toxicity of proton PBI.METHODS AND MATERIALS: This multi-center Proton Collaborative Group phase II trial (PCG BRE007-12) recruited women age ≥50 years with AJCC stage 0–2, node negative, ER-positive, ≤3cm, non-lobular invasive breast cancer or ductal carcinoma in situ who underwent breast- conserving surgery. Proton PBI was delivered to 40Gy(RBE) over 2 weeks. All received uniform scanning proton therapy except 1 receiving passively scattered protons; ≥2 treatment fields were used. Primary endpoint was progression- free survival. Adverse events were prospectively graded using CTCAEv4.0. BTCOS was used to assess patient-reported quality of life (PRQOL) endpoints and cosmesis (scored 1–4).RESULTS: Thirty-eight evaluable patients (left-sided=21 [55%]) were enrolled between 2/2013–11/2016. Median tumor size was 0.95cm. Median age was 67 years (50–79). At a median follow-up of 35 months (12–62), all patients were alive, and no patient had local, locoregional or distant disease progression. One patient developed new ER-negative invasive ductal carcinoma of the contralateral breast. Twenty-nine patients (76.3%) received hormonal therapy. Seven grade 2 toxicities occurred (radiation dermatitis=1; lymphedema=1; hot flashes=3; dyspnea=1; fatigue=1). No grade ≥3 toxicities attributable to radiotherapy were observed. Five patients (13%) assigned a BTCOS score of 4 at 1- or 3-year follow-up. Median heart volume receiving 5Gy (V5Gy) was 0%; lung V20Gy was 0% and V10Gy 0.17%.CONCLUSION: At 3 years, proton PBI provides 100% cancer control for early stage, ER-positive breast cancer with minimal toxicity and acceptable long-term PRQOL. These findings, together with excellent dosimetric sparing of critical organs achieved with proton PBI, provide evidence that protons are safe and effective for PBI.INTRODUCTION: The treatment of targets with considerable motion is a big challenge in proton therapy, especially for pencil beam scanning (PBS) technique. The interplay effect can be significant particularly for small target treated with hypofractionation or SBRT. Deep inspiration breath hold (DIBH) can't apply to all patients, especially for lung patients with poor lung function. Here we present two SBRT lung cases treated with breath hold at the end of exhale (EoE) using PBS proton therapy.METHODS AND MATERIALS: Two patients prescribed to receive SBRT lung treatment of 55 Gy in 5 fractions show target motion more than 1.5 cm on their 4DCT images. Both patients could not tolerate DIBH. Repeated CT scans were performed with patient holding their breath at EoE using Anzai respiratory gating system. A 4D movie was created from these BH scans to check the BH reproducibility. An average BH scan was used as the planning CT. Robust optimization was used on all BH scans with 4% range uncertainty and 5 mm setup uncertainty. Layer repainting and volumetric repainting were also used to minimize interplay effects.RESULTS: Both patients tolerated BH well at EoE. Daily CBCT and verification CT (VFCT) showed good reproducibility of the target location. The average BH duration was around 15 seconds and patient could quickly resume the BH after resting two or three regular breaths. The clinic plan was forward calculated on the VFCT and both target and OAR DVHs remained similar to the nominal plan.CONCLUSIONS: BH at EoE is a viable option for patient who can't tolerate DIBH, which reduces target motion and mitigate the interplay effect of PBS treatment. Multiple factors should be considered carefully when implementing this technique in clinic, for example, gating system selection, BH reproducibility, image verification during treatment, treatment plan robustness, and beam delivery time etc.BACKGROUND: Proton therapy may increase the tolerability/effectiveness of concurrent chemo-radiotherapy for locally advanced cancers but is unproven and generally not covered by private insurers. There is very little data on the comparative effectiveness of proton vs. photon chemo-radiotherapy among private insurance patients to guide payers on coverage policies for protons.METHODS AND MATERIALS: We conducted a comparative effectiveness study of adult non-metastatic cancer patients with non-Medicare private insurance treated with curative-intent proton chemo-radiotherapy vs. photon chemo-radiotherapy from 2011–2016 at Penn. The choice of radiation modality was largely determined by the insurer's proton coverage policy. Data on adverse events (AEs) and survival were gathered prospectively using standardized templates. Primary endpoint was 90-day AEs associated with unplanned hospitalizations (CTCAEv4 grade ≥3 AEs). Secondary endpoints included 90-day grade ≥2 AEs, decline in ECOG performance status during treatment, disease-free survival (DFS), and overall survival (OS). Modified Poisson regression models with inverse propensity score weighting were used for adverse event outcomes and weighted Cox proportional hazards models were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach.RESULTS: 920 patients were included (178 proton/742 photon). Median age was 57. Disease sites included H&N(25 proton/296 photon); CNS(44/128); lung(41/120), upper GI(34/78), and lower GI/GYN(34/120). Race, Charlson-Deyo comorbidity score, BMI, baseline toxicity, and baseline performance status were similar (p>0.05 for all). In propensity score weighted-analyses, proton chemo-radiotherapy was associated with significantly lower relative risk (RR) of 90-day grade ≥3 AEs (RR 0.51, 95%CI 0.32–0.81, p<0.01) and 90-day grade ≥2 AE's (RR 0.91, 95%CI 0.83–0.99, p=0.03). Decline in performance status (RR 0.85, 95%CI 0.70–1.04, p=0.11) and adjusted DFS and OS all favored proton therapy, but the differences were not statistically significant.CONCLUSIONS In adults with locally advanced cancer who have private insurance, proton chemo-radiotherapy was associated with significantly reduced acute adverse events causing unplanned hospitalizations, with similar DFS and OS.BACKGROUND: Definitive chemoradiation (CRT) for anal squamous cell carcinoma (SCC) is curative for most patients. Despite the high conformality of x-ray therapy most patients experience at least grade 2 (G2) acute toxicity as demonstrated in RTOG 0529. Proton beam therapy (PBT) offers significant dosimetric sparing of normal organs in lower dose ranges that may reduce toxicity although there is a lack of published clinical outcomes.METHODS AND MATERIALS: We retrospectively compared acute toxicity outcomes of patients treated