Purpose/Objective(s)Stereotactic body radiotherapy (SBRT) for isolated lymph node recurrence has been shown to have good rates of local control (LC) in gynecological cancers. However there exists the risk of toxicities to nearby organs. This single institution, retrospective outcome and dosimetric analysis assesses treatment response, associated GI and GU toxicities and associated characteristics for improved or worsened outcomes with proton based SBRT, hypothesizing that there will be low rates of toxicities while maintaining beneficial outcomes.Materials/MethodsAdult patients diagnosed with primary gynecologic malignancy with isolated nodal recurrence treated with proton SBRT from 2006-2021 at a single institution were included. Toxicities were evaluated using RTOG/EORTC and CTCAE grading. Descriptive statistics were used to describe characteristics associated with local recurrence, toxicity, and survival.ResultsFourteen patients with 21 nodal lesions were treated with 19 courses of proton SBRT. Median age was 64.5 (range: 47-78) years at time of initial cancer diagnosis and median of 66.0 (range: 51- 80) years at initial lymph node recurrence. Patients recurred within an average of 13.00 (range: 0.66- 31.41) months from end of initial treatment. Primary cancer sites included endometrium (n= 9), cervix (n= 2), ovary (n= 2), and vagina (n= 2). SBRT doses ranged from 30- 50 Gy (median 40 Gy) in 5-15 fractions with mean BED (alpha beta 10) of 69.93 (range: 48.00- 100.00) and mean BED (alpha beta 3) of 139.95 (range: 72.00- 216.67). Nodal locations treated included para-aortic (n= 7), pelvis (n= 5), iliacs (n= 4), and distant nodes (n= 3, supraclavicular, perirectal, periadrenal). Three pelvic and iliac lesions recurred locally at a median of 2.9 months (range 1.25-29.23) and 50% of patients developed local or distant recurrence. Local control at 3 months, 6 months, 1 year, and 2 years was 84.6%, 83.3%, 81.8%, and 70.0% respectively. Local recurrence free survival (LRFS) at 1 year and 2 years was 80.0%, 75.0% and overall survival (OS) was 54.5%, 44.4% respectively. Six patients developed grade 1 or 2 GI treatment related toxicity (Grade 1: 3, Grade 2: 3). 2 patients developed grade 1 GU toxicity. There were no GI grade 3-5 toxicities or GU grade 2-5 toxicities. Average Dmax to bladder was 14.42 Gy (median 18.62 Gy), range (0.6- 30.6). Average rectum Dmax was 15.75 Gy (range: 0.1- 34.2), median: 15.8 Gy. Median small bowel D2cc was 27 Gy (range: 10- 50.5)ConclusionPatients treated with proton SBRT had excellent rates of LC and LRFS and low rates of GI and GU toxicity. Dosimetric analysis also demonstrates low dose to nearby OARs. Based on these findings, Phase I/II trials evaluating dose escalation using proton techniques to further improve local control of isolated nodal recurrences should be considered.

Purpose/Objective(s) Chordomas are rare tumors that arise from embryonic remnants of the notochord and can arise anywhere along the spine or the base of skull. This condition is even more uncommon within the pediatric population, and standard of care treatment includes maximal safe resection with subsequent radiation. The use of proton radiation allows for a conformal delivery of radiation dose that potentially minimizes the exposure of sensitive nearby structures to harmful treatment effects. The purpose of this study is to evaluate the long-term survival and toxicity of pediatric patients with base of skull or cervical spine chordomas treated at this institution with proton-based radiation therapy. Materials/Methods This IRB-approved single-institution study examines a cohort of 36 pediatric patients (≤ 18 years old) with 39 lesions treated with proton radiation between 1994 and 2016. Patients were included if they were treated with definitive intent and had at least five years of time since completing radiation treatment. Median age at treatment of patients was 10.9 years old. 79% of lesions received subtotal resection, while 21% received gross total resection. 10 patients received chemotherapy. The vast majority of tumors was treated to 72-77.4Gy in 40-43 fractions. Two patients were treated to 66.6Gy in 37 fractions. Results Median follow-up time was 100 months. The 5-year overall survival for the entire cohort was 26/36 (72%), further stratified by gender to reveal 68% in the female cohort and 75% in the male cohort. Seven patients (19%) developed distant metastases and subsequent passed away from their disease. GTV over size of 25cc and poorly differentiated histology were associated with decreased overall survival and local control. Of the 30 patients with base of skull lesions, at most recent follow-up, 15 patients (50%) had ototoxicity with 12 of those cases related to adjuvant treatment. 17 patients had confirmed pituitary dysfunction or required pituitary hormone replacement at some timepoint after treatment, 7 patients had no dysfunction, 5 patients died without evidence of pituitary dysfunction, 1 patient did not have pituitary function tests available. No instances of brain or brainstem necrosis were seen. Of the 21 survivors, 20 were either in school or employed with no cognitive or learning disabilities present. Conclusion This single-institution experience shows the efficacy and safety of proton radiation in pediatric patients with chordomas. Limitations include small number of patients and retrospective nature of the study. Future directions include analysis at 10-year follow-up and further evaluation of long-term toxicity.

B.K. Lee: Employee; Amgen. L.N. Loredo: None. J.D. Slater: None.

Ipsilateral radiation therapy is well tolerated with IMRT and proton based radiation therapy. Fewer patients underwent PEG tube placement in the proton cohort, however these results should be further validated with prospective patient-toxicity centered studies.

Epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer. EGFR expression plays a potentially important role in modulation of tumor sensitivity to either chemotherapy or radiotherapy. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR/HER1. A phase II trial was conducted to explore the efficacy of a regimen utilizing erlotinib and proton therapy. Patients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas, as defined by 2012 NCCN guidelines, were included. Patients received neoadjuvant gemcitabine 1000 mg/m2 IV on days 1, 8, 15, 22, 29, 36, and 43 and erlotinib 100 mg by mouth every day for 1-43 days (GE). If there was no evidence of metastatic disease after GE, then patients preceded with proton therapy to 50.4 Gy in 28 fractions with concurrent capecitabine 825 mg/m2 twice per day (PCT). This was followed with maintenance oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice per day on days 2 to 15 (CapOx) for 4 cycles. The primary study objective was 1-year overall survival (OS). The benchmark was 43% 1-year survival as demonstrated in RTOG/NRG 98-12. The Kaplan-Meier method was used to estimate the one-year OS and the median OS and progression-free survival (PFS). The study enrolled 9 patients (5 male) ages 47-81 years old (median 62) between January 2013 and March 2016, when the trial was closed due to poor accrual. The 1-year OS rate was 55.6% (95% CI, 31% to 99%). The median OS was 14.1 months (95% CI, 11.4-NE) and the median PFS was 10.8 months (95% CI, 7.44-NE). A majority of patients completed PCT and GE, but only 33.3% completed the four cycles of CapOx. A third of patients experienced grade 3 toxicities, which were all hepatic along with one patient who also had grade 3 diarrhea. There were no grade 4 or 5 toxicities. Four patients were enrolled with borderline resectable disease (NCCN), three of which were eligible for pancreaticoduodenectomy after GE and PCT treatment. One of two patients who underwent resection had a negative margin. This regimen for locally advanced pancreatic cancer exceeded the pre-specified benchmark and was safe and well tolerated. Additional investigations utilizing more current systemic treatment regimens with proton therapy are warranted.

Background: A phase I trial to determine the maximum tolerated dose (MTD) of Proton stereotactic body radiation therapy (SBRT) for liver metastases in anticipation of a subsequent phase II study. Methods: An institutional IRB approved phase I clinical trial was conducted. Eligible patients had 1-3 liver metastases measuring less than 5 cm, and no metastases location within 2 cm of the GI tract. Dose escalation was conducted with three dose cohorts. The low, intermediate, and high dose cohorts were planned to receive 36, 48, and 60 respectively to the internal target volume (ITV) in 3 fractions. At least 700 mL of normal liver had to receive <15. Dose-limiting toxicity (DLT) included acute grade 3 liver, intestinal or spinal cord toxicity or any grade 4 toxicity. The MTD is defined as the dose level below that which results in DLT in 2 or more of the 6 patients in the highest dose level cohort. Results: Nine patients were enrolled (6 male, 3 female): median age 64 years (range, 33-77 years); median gross tumor volume (GTV) 11.1 mL (range, 2.14-89.3 mL); most common primary site, colorectal (5 patients). Four patients had multiple tumors. No patient experienced a DLT and dose was escalated to 60 in 3 fractions without reaching MTD. The only toxicity within 90 days of completion of treatment was one patient with a grade 1 skin hyperpigmentation without tenderness or desquamation. Two patients in the low dose cohort had local recurrence and repeat SBRT was done to previously treated lesions without any toxicities. Conclusions: Biologically ablative Proton SBRT doses are well tolerated in patients with limited liver metastases with no patients experiencing any grade 2+ acute toxicity. Results from this trial provide the grounds for an ongoing phase II Proton SBRT study of 60 over 3 fractions for liver metastases.

To evaluate local control outcomes of liver metastases treated with proton stereotactic body radiation therapy (SBRT). Secondary objectives include evaluation of toxicity. Patients diagnosed with metastatic disease to the liver treated with proton SBRT between 2012-2017 per NRG-BR001 study of SBRT for the treatment of multiple metastases were included. Tumor motion was accounted for using either respiratory management or 4D CT scan. Important aspects of plan assessment included dose restricting when close to bowel and keeping V15 (volume of liver receiving at least 15 Gy) or V21 less than 700cc's of normal liver in 3 or 5 fraction plans respectively. In-field local control was evaluated according to RECIST 1.1 criterion. Radiation induced liver disease was evaluated using CTCAE 5.0 criteria. A total of 41 patients with 80 lesions were included in this analysis with a median age of 65.5 years (range 33-87). Dose/fractionation included 50Gy / 5 fractions (19%), 30Gy / 5 fractions (16%), and 30Gy / 3 fractions (16%). The primary cancer site was 51% colorectal, 17% breast, and 33% other. The mean number of metastases treated was 1.7 (range 1-5) with mean tumor diameter of 2.7 cm ± 1.6 cm (range 0.7 – 7.3). With a mean follow up of 14.5 months (range 1 – 44), local control at 6 months and 1 year was 92% and 75%, respectively. No radiation induced liver disease was detected. Grade 1 and grade 2 toxicities were 38% and 6% respectively. No patient developed grade 3 or higher toxicity. Predicted liver toxicity was minimal, with median V15 of 205cc (interquartile range; IQR 137-235) and median V21 of 155cc (IQR 64 – 236) for 3 and 5 fraction plans respectively. Proton SBRT for liver metastases demonstrated a high rate of local tumor control with minimal toxicity. The integral dose advantage allows patients to have multiple courses of full dose therapy while still maintaining liver dose constraints. This is especially important, as out of field liver metastases are one of the most common sites of recurrence or progression in these patients.

Long-term quality of life (QoL) is a salient factor in assessing outcomes of breast conservation therapy for patients with early-stage breast cancer. This study compares patient-reported QoL outcomes among women with stage 0-II disease treated with partial mastectomy followed by partial-breast proton irradiation (PBPI) or whole-breast photon (WBI). : PBPI subjects were recruited from previous participation in an institutional prospective clinical trial. WBI subjects were recruited from a registry maintained at the same institution. QoL tools completed included the Harvard Cosmesis Scale (HCS), Breast Cancer Treatment Outcome Scale (BCTOS), Brief Fatigue Inventory (BFI), Medical Outcomes Study (MOS) Short Form, and Body Image Scale (BIS). 180 subjects received surveys with 142 being completed and returned yielding a 79% participation rate. 13 were determined to be ineligible due to bilateral disease, disease recurrence, metastatic disease, or other serious medical co-morbidities. 129 participants completed QoL and were included for evaluation, 72 following PBPI and 57 following WBI. Median time from treatment was 7.4 years (PBPI) and 6.3 years (WBI). The two groups were well matched for age, weight, marital status, race, education, employment, recent health status, stage, tumor size, extent of surgery, and use of adjuvant systemic therapy. Significant differences favoring the proton group were seen for several domains. The HCS showed higher cosmetic mean scores for PBPI 3.4 vs WBI 2.4 (p<0.001). BCTOS results showed improved weighted BCTOS (5.5 vs 7.6, p<0.001), cosmetic BCTOS (11.6 vs 15.0, p<0.001), and BS pain (4.2 vs 5.3, p=0.005) for PBPI vs WBI respectively. BFI demonstrated reduced fatigue (2.2 vs 3.8, p=0.002) with less interference with daily general activities (1.7 vs 2.8, p=0.017) for PBPI vs WBI. MOS survey resulted in statistically significant improved perception of general health with improved emotional and social functioning for PBPI. BIS resulted in improved overall score favoring PBPI (12.1 vs 14.2, p=0.009). Patients' responses suggest that partial-breast proton radiotherapy is associated with higher long term overall QoL across multiple domains when compared to a comparable cohort of patients treated with whole breast radiotherapy.

Background: The goal of this study is to determine whether a phase or reconstruction of a 10-phase 4 dimensional computed tomography (4D CT) scan can be used as the primary planning scan for proton treatment of the pancreas, thus eliminating the need for second a slow CT or free breathing CT. Methods: Ten patients with pancreatic adenocarcinoma were simulated with 4D CT and a proton treatment plan generated based upon one of three primary planning scans, the T0 phase, T50 phase or average reconstruction. These plans were then exported to each of the remaining phases of the 4D CT and the dose to 95% of the target (D95) calculated. Plans were deemed adequate if the D95 remained at 99% of the prescribed dose or greater. Results: For the ten patients in this study anterior abdominal motion was found to range from 2-27 mm (mean 7.50 +/- 6.79 mm). For 9 of 10 patients the anterior abdominal motion was <= 8 mm and all three primary planning scans provided adequate target coverage, resulting in minimum D95 coverage per plan of T0_plan 99.7%, T50_plan 99.3% and AVE_plan 99%. However no plan provided adequate target coverage on the single patient with the largest anterior abdominal motion, 27 mm, and cranio-caudal motion, 20 mm, with minimum D95 values of T0_plan 96.3%, T50_plan 68%, and AVE_plan 68%. Conclusions: The primary plans tested based up on the T0, T50 and average reconstructions provided adequate D95 coverage throughout the respiratory cycle as long as the anterior abdominal motion was <= 8 mm and can be considered for use as the primary proton planning scan.

To determine the maximum tolerated dose (MTD) of stereotactic body proton therapy (SBPT) for liver metastases in anticipation of a subsequent phase II study. Although phase I studies have shown safety with photon based treatments, similar clinical safety profile and tolerability with proton based therapy has not been reported. An IRB approved phase I clinical trial was conducted. Eligible patients had 1-3 liver metastases measuring less than 5cm, and no CNS metastases, tense ascites requiring frequent paracentesis or metastases location within 2cm of the GI tract. The initial cohort received 36 GyE to the planning target volume (PTV) in 3 fractions. Subsequent cohorts received 48 GyE in 3 fractions and finally 60 GyE in 3 fractions, the final chosen maximum dose. At least 700mL of normal liver had to receive <15 GyE. Dose-limiting toxicity (DLT) included acute grade 3 liver, intestinal or spinal cord toxicity or any grade 4 toxicity. The MTD is defined as the dose level below that which results in DLT in 2 or more of the 6 patients in the highest dose level cohort. Nine patients were enrolled (6 male, 3 female): median age 64 years (range, 33-77 years); median gross tumor volume 11.1 ml (range, 2.14-89.3 ml); most common primary site, colorectal (5 patients). Four patients had multiple tumors. No patient experienced a DLT and dose was escalated to 60 GyE in 3 fractions without reaching MTD. The only toxicity within 90 days of completion of treatment was one patient with a grade 1 skin hyperpigmentation without tenderness or desquamation. Two patients in the first cohort had local recurrence and repeat SBPT was done to previously treated lesions without any reported toxicities. Biologically ablative SBPT doses are well tolerated in patients with limited liver metastases with no patients experiencing any grade 2+ acute toxicity. Results from this trial provide the grounds for an ongoing phase II SBPT study of 60 GyE over 3 fractions for liver metastases.

A collaborative approach to treating intracranial arteriovenous malformations is vital to successful management of large symptomatic arteriovenous malformations (AVM). Stereotactic proton therapy (SPT) acts as a key component, along with surgical resection and neurovascular embolization, attempting to decrease morbidity and mortality. This study aims to evaluate the obliteration rate, acute complications, and hemorrhage rate in patients treated with 2 fraction SPT for intracranial AVMs within a multimodal therapeutic approach. From 1993 to 2014, 124 patients were treated for intracranial AVMs with 2 fraction SPT as part of a multidisciplinary effort for treatment of these lesions as part of a registry trial. Asymptomatic patients were not treated. Patients presented with headache (n = 59; 48%); seizure (n = 56; 45%); increasing neurologic deficit (n = 83; 67%); and hemorrhage (n = 61; 49%). Many patients had received prior treatment with embolization (n = 68; 55%), surgical resection (n = 26, 21%), or radiosurgery (n = 25; 20%). The median AVM nidus at time of SPT was 19.8 cc (range 0.3-191.2), with 52% in eloquent regions (Brainstem, Basal Ganglia/Thalamus, Motor Strip). The median prescription dose was 25 GyE (range 16-27.5 GyE). Follow up was done with MRI/MRA every 6-12 months and planned cerebral angiogram to confirm obliteration or after 3 years post SPT. Of the 124 patients, 9 were lost to follow up, while the remaining 115 had a median follow-up of 92.9 months. Thirty-seven patients had additional therapy, some of which were planned, including embolization (n = 16), surgery (n = 18), or radiosurgery including additional SPT (n = 26). Of patients with at least 24 months follow up, the total obliteration rate was 30% (n = 29) with a median time to obliteration of 39.7 months (range 14-196.2) and partial obliteration rate was 46% (n = 45) with median time of 22 months (range 4.5-137.3). The most common acute complications were headaches (n = 18; 16%); seizures (n = 11; 10%); and transient neurological deficits (n = 15; 13%). Twenty-four patients (21%) experienced post treatment hemorrhage with the median time to hemorrhage of 41.7mths (range 1.8-204.2). Ten patients (9%) died after treatment, with 9 of the patients dying after AVM hemorrhage and 1 from a primary tumor. The management of large, symptomatic, and/or eloquent AVMs requires the expertise and collaborative approach of the radiation oncologist, neurosurgeon, and neurointerventionalist. Two-fraction SPT is a key component in this multimodal approach, with this study showing effective obliteration while mitigating potential adverse effects.

Purpose: To investigate the use of magnetic focusing for small field proton irradiations. It is hypothesized that magnetic focusing will provide significant dose distribution benefits over standard collimated beams for fields less than 10 mm diameter. Methods: Magnets consisting of 24 segments of radiation hard samarium-cobalt adhered into hollow cylinders were designed and manufactured. Two focusing magnets were placed on a positioning track on our Gantry 1 treatment table. Proton beams with energies of 127 and 157 MeV, 15 and 30 mm modulation, and 8 mm initial diameters were delivered to a water tank using single-stage scattering. Depth dose distributions were measured using a PTW PR60020 diode detector and transverse profiles were measured with Gafchromic EBT3 film. Monte Carlo simulations were also performed - both for comparison with experimental data and to further explore the potential of magnetic focusing in silica. For example, beam spot areas (based on the 90% dose contour) were matched at Bragg depth between simulated 100 MeV collimated beams and simulated beams focused by two 400 T/m gradient magnets. Results: Preliminary experimental results show 23% higher peak to entrance dose ratios and flatter spread out Bragg peak plateaus for 8 mm focused beams compared with uncollimated beams. Monte Carlo simulations showed 21% larger peak to entrance ratios and a ∼9 fold more efficient dose to target delivery compared to spot-sized matched collimated beams. Our latest results will be presented. Conclusion: Our results suggest that rare earth focusing magnet assemblies could reduce skin dose and beam number while delivering dose to nominally spherical radiosurgery targets over a much shorter time compared to unfocused beams. Immediate clinical applications include those associated with proton radiosurgery and functional radiosurgery of the brain and spine, however expanded treatment sites can be also envisaged.

Purpose:To investigate the use of magnetic focusing for small volume proton radiosurgery targets using a triplet combination of quadrupole rare earth permanent magnet Halbach cylinder assembliesMethods:Fourteen quadrupole magnets consisting of 24 segments of radiation hard samarium‐cobalt adhered into k=3 Halbach cylinders with various field gradients (100 to 250 T/m) were designed and manufactured. Triplet combinations of the magnets were placed on a positioning track on our Gantry 1 treatment table. Unmodulated 127 MeV proton beams with initial diameters of 3 to 20 mm were delivered to a water tank using single‐stage scattering. Depth and transverse dose distributions were measured using a PTW PR60020 diode detector and EBT3 film, respectively. This data was compared with unfocused passively collimated beams. Monte Carlo simulations were also performed ‐ both for comparison with experimental data and to further investigate the potential of triplet magnetic focusing.Results:Experimental results using 150 T/m gradient magnets and 15 to 20 mm initial diameter beams show peak to entrance dose ratios that are ∼ 43 to 48 % larger compared with spot size matched 8 mm collimated beams (ie, transverse profile full‐widths at 90% maximum dose match within 0.5 mm of focused beams). In addition, the focusing beams were ∼ 3 to 4.4 times more efficient per MU in dose to target delivery. Additional results using different magnet combinations will also be presented.Conclusion:Our results suggest that triplet magnetic focusing could reduce entrance dose and beam number while delivering dose to small (∼≤ 10 mm diameter) radiosurgery targets in less time compared to unfocused beams. Immediate clinical applications include those associated with proton radiosurgery and functional radiosurgery of the brain and spine, however other treatment sites can be also envisioned.This project was sponsored with funding from the Department of Defense (DOD# W81XWH‐BAA‐10‐1).

BACKGROUND Pancreatic cancer is a highly aggressive malignancy. Chemoradiotherapy (CRT) is utilized in many cases to improve locoregional control; however, toxicities associated with radiation can be significant given the location of the pancreas. RTOG 0848 seeks to evaluate chemoradiation using either intensity-modulated radiation therapy (IMRT) or 3D conformal photon radiotherapy (3DCRT) modalities as an adjuvant treatment. The purpose of this study is to quantify the dosimetric changes seen when using IMRT or 3D CRT photon modalities, as well as proton radiotherapy, in patients receiving CRT for cancer of the pancreas treated per RTOG 0848 guidelines. MATERIALS Ten patients with pancreatic head adenocarcinoma treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using IMRT and 3DCRT as well as proton radiotherapy were created for each patient. All planning volumes were created per RTOG 0848 protocol. Dose-volume histograms (DVH) were calculated and analyzed in order to compare plans between the three modalities. The organs at risk (OAR) evaluated in this study are the kidneys, liver, small bowel, and spinal cord. RESULTS There was no difference between the IMRT and 3DCRT plans in dose delivered to the kidneys, liver, or bowel. The proton radiotherapy plans were found to deliver lower mean total kidney doses, mean liver doses, and liver D1/3 compared to the IMRT plans. The proton plans also gave less mean liver dose, liver D1/3, bowel V15, and bowel V50 in comparison to the 3DCRT. CONCLUSIONS For patients receiving radiotherapy per ongoing RTOG 0848 for pancreatic cancer, there was no significant difference in normal tissue sparing between IMRT and 3DCRT treatment planning. Therefore, the choice between the two modalities should not be a confounding factor in this study. The proton plans also demonstrated improved OAR sparing compared to both IMRT and 3DCRT treatment plans.