Prospective evaluation of patient-reported outcomes of invisible ink tattoos for the delivery of external beam radiation therapy: the PREFER trial.

Introduction: Invisible ink tattoos (IITs) avoid cosmetic permanence of visible ink tattoos (VITs) while serving as more reliable landmarks for radiation setup than tattooless setups. This trial evaluated patient-reported preference and feasibility of IIT implementation. Methods and materials: In an IRB-approved, single institution, prospective trial, patients receiving proton therapy underwent IIT-based treatment setup. A survey tool assessed patient preference on tattoos using a Likert scale. Matched patients treated using our institutional standard tattooless setup were identified; treatment times and image guidance requirements were evaluated between tattooless and IIT-based alignment approaches. Distribution differences were estimated using Wilcoxon rank-sum tests or Chi-square tests. Results: Of 94 eligible patients enrolled, median age was 58 years, and 58.5% were female. Most common treatment sites were breast (18.1%), lung (17.0%) and pelvic (14.9%). Patients preferred to receive IITs versus VITs (79.8% pre-treatment and 75.5% post-treatment, respectively). Patients were willing to travel farther from home to avoid VITs versus IITs (p<0.01). Females were willing to travel (45.5% vs. 23.1%; p=0.04) and pay additional money to avoid VITs (34.5% vs. 5.1%; p<0.01). Per-fraction average +treatment time and time from on table/in room to first beam were shorter with IIT-based vs. tattooless setup (12.3min vs. 14.1min; p=0.04 and 24.1min vs. 26.2min; p=0.02, respectively). Discussion: In the largest prospective trial on IIT-based radiotherapy setup to date, we found that patients prefer IITs to VITs. Additionally, IIT-based alignment is an effective and efficient strategy in comparison with tattooless setup. Standard incorporation of IITs for patient setup should be strongly considered.

Reirradiation With Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial.

Purpose: Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT. Methods and Materials: Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start. Results: Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported. Conclusions: In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

Comparative Evaluation of Proton Therapy and Volumetric Modulated Arc Therapy for Brachial Plexus Sparing in the Comprehensive Reirradiation of High-Risk Recurrent Breast Cancer.

Purpose: Recurrent or new primary breast cancer requiring comprehensive regional nodal irradiation after prior radiation therapy (RT) to the supraclavicular area and upper axilla is challenging due to cumulative brachial plexus (BP) dose tolerance. We assessed BP dose sparing achieved with pencil beam scanning proton therapy (PBS-PT) and photon volumetric modulated arc therapy (VMAT). Methods and Materials: In an institutional review board-approved planning study, all patients with ipsilateral recurrent breast cancer treated with PBS-PT re-RT (PBT1) with at least partial BP overlap from prior photon RT were identified. Comparative VMAT plans (XRT1) using matched BP dose constraints were developed. A second pair of proton (PBT2) and VMAT (XRT2) plans using standardized target volumes were created, applying uniform prescription dose of 50.4 per 1.8 Gy and a maximum BP constraint <25 Gy. Incidence of brachial plexopathy was also assessed. Results: Ten consecutive patients were identified. Median time between RT courses was 48 months (15-276). Median first, second, and cumulative RT doses were 50.4 Gy (range, 42.6-60.0), 50.4 Gy relative biologic effectiveness (RBE) (45.0-64.4), and 102.4 Gy (RBE) (95.0-120.0), respectively. Median follow-up was 15 months (5-33) and 18 months for living patients (11-33) Mean BP max was 37.5 Gy (RBE) for PBT1 and 36.9 Gy for XRT1. Target volume coverage of V85% (volume receiving 85% of prescription dose), V90%, and V95% were numerically lower for XRT1 versus PBT1. Similarly, axilla I-III and supraclavicular area coverage were significantly higher for PBT2 than XRT2 at dose levels of V55%, V65%, V75%, V85%, and V95%. Only axilla I V55% did not reach significance (P = .06) favoring PBS-PT. Two patients with high cumulative BPmax (95.2 Gy [RBE], 101.6 Gy [RBE]) developed brachial plexopathy symptoms with ulnar nerve distribution neuropathy without pain or weakness (1 of 2 had symptom resolution after 6 months without intervention). Conclusions: PBS-PT improved BP sparing and target volume coverage versus VMAT. For patients requiring comprehensive re-RT for high-risk, nonmetastatic breast cancer recurrence with BP overlap and reasonable expectation for prolonged life expectancy, PBT may be the preferred treatment modality.

Prognostic implications of HER2NEU-low in metastatic breast cancer.

INTRODUCTION: We explored characteristics and clinical outcomes of HER2-negative and HER2-low metastatic breast cancers using real-world data. METHODS: We queried the National Cancer Database to identify MBC patients that were HER2-low or HER2-negative per immunohistochemical staining. A binomial regression analysis identified demographic and clinical correlates of each subtype. A Cox multivariable regression analysis (MVA) and propensity-match analysis were performed to identify correlates of survival. RESULTS: Excluding missing data, 24,636 MBC patients diagnosed between 2008 and 2015 were identified; 27.9% were HER2-negative and 72.1% were HER2-low. There were no relevant demographic differences between the groups. HER2-low tumors were half as likely to have concomitant hormone receptor-positive status (p < 0.01). The 3-year survival rate among hormone receptor-negative patients was 33.8% for HER2-low and 32.2% for HER2-negative (p < 0.05), and 60.9% and 55.6% in HER2-low and HER2-negative cases among hormone receptor-positive patients (p < 0.05), respectively. HER2-low cases were associated with better survival on MVA (HR =0.95, 95% CI 0.91-0.99) and remained superior with propensity-matching (HR = 0.92, 95% CI 0.89-0.96). In a subset analysis isolated to hormone receptor-positive cases, HER2-low remained correlated with improved survival (HR = 0.93, 95% CI 0.89-0.98) with propensity-matched MVA. Correlates of worse survival include older age as a continuous variable (HR = 1.02, 95% CI 1.02-1.02) and Black race (HR = 1.26, 95% CI 1.20-1.32) [all p < 0.01]. CONCLUSIONS: In the largest such analysis performed to date, our study demonstrates a small but statistically significant association with improved survival for HER2-low tumors compared to HER2-negative tumors in MBC.

Accelerated Partial Breast Irradiation for HER2-Positive Early-Stage Breast Cancer.

PURPOSE: HER2-positive (HER2+) breast cancer historically exhibited the most adverse local outcomes and, consequently, has had limited representation among trials of partial breast irradiation (PBI). We hypothesized that with contemporary HER2-targeted agents, patients may now exhibit excellent disease control outcomes after adjuvant PBI. METHODS AND MATERIALS: Using a prospectively maintained institutional database, we identified patients with HER2+ breast cancer treated with breast conserving surgery (BCS) and PBI from 2000 to 2022. Salient clinicopathologic and treatment parameters were collected. All patients received external beam PBI to 40 Gy in 10 daily fractions. Cumulative incidence functions were calculated to estimate the incidence of local recurrence (LR) with the competing risk of death. RESULTS: We identified 1248 patients who underwent PBI at our institution, of whom the study cohort comprised 52 (4%) with HER2+ breast cancer (median age, 64 years; range, 44-87). Nearly all had T1 tumors (98%; median size, 12 mm [range, 1-21 mm]). Most had estrogen receptor positive disease (88%), and all patients had negative surgical margins. Nearly all underwent sentinel node biopsy (94%), with the remainder undergoing no surgical axillary evaluation. Forty-two (81%) received chemotherapy; 40 (77%), hormone therapy; and 42 (81%), HER2-directed therapy, most commonly trastuzumab. At 143.8 person-years of follow-up (range, 7-226 months for each patient), we observed 2 LR events at 14 and 26 months, respectively, yielding a 2-year LR rate of 3.8%. No regional or distant recurrences were observed, nor were any breast-specific mortality events. Two deaths were observed, both without evidence of disease. CONCLUSIONS: Among a cohort of patients with HER2+ early-stage breast cancer managed with BCS and PBI, we observed a 2-year LR rate of 3.8%, with no regional or distant recurrences and excellent overall survival. These findings require confirmation with longer follow-up among larger cohorts but appear consistent with the excellent results of contemporary randomized trials of PBI unselected for HER2 status.

Proton Reirradiation for High-Risk Recurrent or New Primary Breast Cancer.

Radiotherapy is an integral component of multidisciplinary breast cancer care. Given how commonly radiotherapy is used in the treatment of breast cancer, many patients with recurrences have received previous radiotherapy. Patients with new primary breast cancer may also have received previous radiotherapy to the thoracic region. Curative doses and comprehensive field photon reirradiation (reRT) have often been avoided in these patients due to concerns for severe toxicities to organs-at-risk (OARs), such as the heart, lungs, brachial plexus, and soft tissue. However, many patients may benefit from definitive-intent reRT, such as patients with high-risk disease features such as lymph node involvement and dermal/epidermal invasion. Proton therapy is a potentially advantageous treatment option for delivery of reRT due to its lack of exit dose and greater conformality that allow for enhanced non-target tissue sparing of previously irradiated tissues. In this review, we discuss the clinical applications of proton therapy for patients with breast cancer requiring reRT, the currently available literature and how it compares to historical photon reRT outcomes, treatment planning considerations, and questions in this area warranting further study. Given the dosimetric advantages of protons and the data reported to date, proton therapy is a promising option for patients who would benefit from the added locoregional disease control provided by reRT for recurrent or new primary breast cancer.

Safety and efficacy of stereotactic body proton therapy for high-risk lung tumors.

Purpose: Stereotactic body proton therapy (SBPT) is an emerging treatment strategy for lung tumors that aims to combine the excellent local control benefits of ultra-hypofractionation with the physical advantages of protons, which reduce the integral dose to organs at risk (OARs) compared to photons. To date, however, very little data delivering SBPT in 5 or fewer fractions to lung tumors have been reported. Given that photon stereotactic body radiation therapy can struggle to deliver ablative doses to high-risk tumors (i.e., central/ultra-central location, prior in-field radiation, tumor size >5 cm, or the presence of severe pulmonary comorbidities) while adhering to OAR dose constraints, we hypothesized that SBPT would be an effective alternative for patients with high-risk tumors. Methods and Materials: Twenty-seven high-risk patients with 29 lung tumors treated with SBPT at the New York Proton Center between December 2019 and November 2022 were retrospectively identified. Patients were divided into three major subgroups: early-stage non-small cell lung cancer (NSCLC), locally recurrent NSCLC, and metastatic cancer from lung cancer or other histologies. Patient characteristics were reported using descriptive statistics, actuarial methods were used to quantify disease control rates, and toxicities were scored using CTCAE v 5.0. Results: The most common high-risk indications for SBPT were central/ultra-central tumor location (69.0%), severe COPD (48.1%), reirradiation (44.4%), significant pulmonary fibrosis (22.2%), and large tumor size > 5 cm (18.5%). In total, 96.6% of tumors were fully covered by the prescription dose without compromising target coverage. Three-year actuarial rates of local control for early-stage NSCLC, locally recurrent NSCLC, and metastatic patients were 89%, 100%, and 43%, respectively. Three-year actuarial rates of regional control were 89%, 67%, and 86%. Three-year actuarial rates of distant metastasis-free survival were 79%, 100%, and 0%. Two patients (7.4%), both of whom had clinically significant baseline interstitial lung disease and pre-treatment continuous oxygen demand, experienced grade ≥2 pulmonary toxicity (1 grade 3, 1 grade 5). There were no acute or late grade ≥2 toxicities related to esophagitis, cardiac injury, airway injury, pulmonary fibrosis, bronchopulmonary hemorrhage or brachial plexopathy. Conclusions: In the largest study of proton SBRT reported to date, SBPT has a favorable toxicity profile while being an effective approach for treating most high-risk tumors without requiring dose de-escalation or compromising tumor coverage and warrants further investigation.

Advances in treatment planning and management for the safety and accuracy of lung stereotactic body radiation therapy using proton pencil beam scanning: Simulation, planning, quality assurance, and delivery recommendations.

This study presents the clinical experiences of the New York Proton Center in employing proton pencil beam scanning (PBS) for the treatment of lung stereotactic body radiation therapy. It encompasses a comprehensive examination of multiple facets, including patient simulation, delineation of target volumes and organs at risk, treatment planning, plan evaluation, quality assurance, and motion management strategies. By sharing the approaches of the New York Proton Center and providing recommendations across simulation, treatment planning, and treatment delivery, it is anticipated that the valuable experience will be provided to a broader proton therapy community, serving as a useful reference for future clinical practice and research endeavors in the field of stereotactic body proton therapy for lung tumors.

The Applications and Pitfalls of Cone-Beam Computed Tomography-Based Synthetic Computed Tomography for Adaptive Evaluation in Pencil-Beam Scanning Proton Therapy.

PURPOSE: The study evaluates the efficacy of cone-beam computed tomography (CBCT)-based synthetic CTs (sCT) as a potential alternative to verification CT (vCT) for enhanced treatment monitoring and early adaptation in proton therapy. METHODS: Seven common treatment sites were studied. Two sets of sCT per case were generated: direct-deformed (DD) sCT and image-correction (IC) sCT. The image qualities and dosimetric impact of the sCT were compared to the same-day vCT. RESULTS: The sCT agreed with vCT in regions of homogeneous tissues such as the brain and breast; however, notable discrepancies were observed in the thorax and abdomen. The sCT outliers existed for DD sCT when there was an anatomy change and for IC sCT in low-density regions. The target coverage exhibited less than a 5% variance in most DD and IC sCT cases when compared to vCT. The Dmax of serial organ-at-risk (OAR) in sCT plans shows greater deviation from vCT than small-volume dose metrics (D0.1cc). The parallel OAR volumetric and mean doses remained consistent, with average deviations below 1.5%. CONCLUSION: The use of sCT enables precise treatment and prompt early adaptation for proton therapy. The quality assurance of sCT is mandatory in the early stage of clinical implementation.

Pencil Beam Scanning Bragg Peak FLASH Technique for Ultra-High Dose Rate Intensity-Modulated Proton Therapy in Early-Stage Breast Cancer Treatment.

Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications.

Advances and Challenges in Conducting Clinical Trials With Proton Beam Therapy.

Advances in proton therapy have garnered much attention and speculation in recent years as the indications for proton therapy have grown beyond pediatric, prostate, spine, and ocular tumors. To achieve and maintain consistent access to this cancer treatment and to ensure the future viability and availability of proton centers in the United States, a call for evidence has been heard and answered by proton radiation oncologists. Answers provided in this review include the evolution of proton therapy research, rationale for proton clinical trial design, challenges in and barriers to the conduct of proton therapy research, and other unique considerations for the study of proton therapy.

Case Report: Cumulative proton dose reconstruction using CBCT-based synthetic CT for interfraction metallic port variability in breast tissue expanders.

Introduction: Dose perturbation of spot-scanning proton beams passing through a dislocated metallic port (MP) of a breast tissue expander may degrade target dose coverage or deliver excess dose to the ipsilateral lung and heart. The feasibility of utilizing daily cone-beam computed tomography (CBCT)-based synthetic CTs (synCTs) for dose reconstruction was evaluated, and the fractional and cumulative dosimetric impact due to daily MP dislocation is reported. Methods: The synCT was generated by deforming the simulation CT to daily CBCT. The MP structure template was mapped onto all CTs on the basis of daily MP position. Proton treatment plans were generated with two and three fields on the planned CT (pCT, Plan A) and the first verification CT (vCT, Plan B), respectively, for a fractional dose of 1.8 Gy(RBE). Plan A and Plan B were used alternatively, as determined by the daily MP position. The reconstructed fractional doses were calculated with corresponding plans and synCTs, and the cumulative doses were summed with the rigid or deformed fractional doses on pCT and vCT. Results: The planned and reconstructed fractional dose demonstrated a low-dose socket around the planned MP position due to the use of field-specific targets (FSTs). Dose hot spots with >120% of the prescription due to MP dislocation were found behind the planned MP position on most reconstructed fractional doses. The reconstructed cumulative dose shows two low-dose sockets around the two planned MP positions reflecting the two plans used. The doses at the hot spots behind the planned MPs averaged out to 114% of the prescription. The cumulative D95% of the CTV_Chest Wall decreased by up to 2.4% and 4.0%, and the cumulative V20Gy(RBE) of the left lung decreased to 16.1% and 16.8% on pCT and vCT, respectively. The cumulative Dmean of the heart decreased to as low as 0.7 Gy(RBE) on pCT but increased to as high as 1.6 Gy(RBE) on vCT. Conclusion: The robustness of proton plans using FSTs around the magnet in the MP of the tissue expander can be improved by applying multiple fields and plans, which provides forgiveness of dose heterogeneity incurred from dislocation of high-Z materials in this single case.

Proton Bragg Peak FLASH Enables Organ Sparing and Ultra-High Dose-Rate Delivery: Proof of Principle in Recurrent Head and Neck Cancer.

Proton pencil-beam scanning (PBS) Bragg peak FLASH combines ultra-high dose rate delivery and organ-at-risk (OAR) sparing. This proof-of-principle study compared dosimetry and dose rate coverage between PBS Bragg peak FLASH and PBS transmission FLASH in head and neck reirradiation. PBS Bragg peak FLASH plans were created via the highest beam single energy, range shifter, and range compensator, and were compared to PBS transmission FLASH plans for 6 GyE/fraction and 10 GyE/fraction in eight recurrent head and neck patients originally treated with quad shot reirradiation (14.8/3.7 CGE). The 6 GyE/fraction and 10 GyE/fraction plans were also created using conventional-rate intensity-modulated proton therapy techniques. PBS Bragg peak FLASH, PBS transmission FLASH, and conventional plans were compared for OAR sparing, FLASH dose rate coverage, and target coverage. All FLASH OAR V40 Gy/s dose rate coverage was 90-100% at 6 GyE and 10 GyE for both FLASH modalities. PBS Bragg peak FLASH generated dose volume histograms (DVHs) like those of conventional therapy and demonstrated improved OAR dose sparing over PBS transmission FLASH. All the modalities had similar CTV coverage. PBS Bragg peak FLASH can deliver conformal, ultra-high dose rate FLASH with a two-millisecond delivery of the minimum MU per spot. PBS Bragg peak FLASH demonstrated similar dose rate coverage to PBS transmission FLASH with improved OAR dose-sparing, which was more pronounced in the 10 GyE/fraction than in the 6 GyE/fraction. This feasibility study generates hypotheses for the benefits of FLASH in head and neck reirradiation and developing biological models.

Effect of treatment interruptions on overall survival in patients with triple-negative breast cancer.

INTRODUCTION: Currently, there are no data regarding the impact of treatment interruptions during radiotherapy for breast cancer. In this study, we examine the correlation between treatment interruptions during radiotherapy and outcomes in triple-negative breast cancer patients. METHODS: A total of 35 845 patients with triple-negative breast cancer treated between 2010 and 2014 were identified and analyzed from the National Cancer Database. The number of interrupted radiotherapy treatment days was calculated as the difference between the total elapsed days from the start to end of radiation treatment (both initial treatment and boost treatment, when boost was administered) and the total number of expected treatment days, defined as the number of expected treatment days with an addition of 2 weekend days for every multiple of 5 treatment days. Binomial multivariate regression analysis was used to detect correlates of treatment interruptions, and propensity-score matched multivariable Cox proportional hazard models were used to evaluate the association between treatment interruption and overall survival (OS). RESULTS: When modeled as a continuous variable, longer treatment duration was associated with poorer OS (hazard ratio [HR] = 1.023, 95% confidence interval [CI] = 1.015 to 1.031). In reference to 0-1 days of interruption, patients with 2-5 interrupted days (HR = 1.069, 95% CI = 1.002 to 1.140 interrupted days), 6-10 interrupted days (HR = 1.239, 95% CI = 1.140 to 1.348 interrupted days), and 11-15 interrupted days (HR = 1.265, 95% CI = 1.126 to 1.431 interrupted days) experienced increasing likelihood of mortality. CONCLUSION: In the first study of its kind, we report a correlation between treatment interruptions during adjuvant radiotherapy in triple-negative breast cancer and OS.

Proton Therapy for Unresectable and Medically Inoperable Locally Advanced Pancreatic Cancer: Results From a Multi-Institutional Prospective Registry.

Purpose: Compared with photon-based techniques, proton beam radiation therapy (PBT) may improve the therapeutic ratio of radiation therapy (RT) for locally advanced pancreatic cancer (LAPC), but available data have been limited to single-institutional experiences. This study examined the toxicity, survival, and disease control rates among patients enrolled in a multi-institutional prospective registry study and treated with PBT for LAPC. Methods and Materials: Between March 2013 and November 2019, 19 patients with inoperable disease across 7 institutions underwent PBT with definitive intent for LAPC. Patients received a median radiation dose/fractionation of 54 Gy/30 fractions (range, 50.4-60.0 Gy/19-33 fractions). Most received prior (68.4%) or concurrent (78.9%) chemotherapy. Patients were assessed prospectively for toxicities using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Kaplan-Meier analysis was used to analyze overall survival, locoregional recurrence-free survival, time to locoregional recurrence, distant metastasis-free survival, and time to new progression or metastasis for the adenocarcinoma cohort (17 patients). Results: No patients experienced grade ≥3 acute or chronic treatment-related adverse events. Grade 1 and 2 adverse events occurred in 78.7% and 21.3% of patients, respectively. Median overall survival, locoregional recurrence-free survival, distant metastasis-free survival, and time to new progression or metastasis were 14.6, 11.0, 11.0, and 13.9 months, respectively. Freedom from locoregional recurrence at 2 years was 81.7%. All patients completed treatment with one requiring a RT break for stent placement. Conclusions: Proton beam RT for LAPC offered excellent tolerability while still maintaining disease control and survival rates comparable with dose-escalated photon-based RT. These findings are consistent with the known physical and dosimetric advantages offered by proton therapy, but the conclusions are limited owing to the patient sample size. Further clinical studies incorporating dose-escalated PBT are warranted to evaluate whether these dosimetric advantages translate into clinically meaningful benefits.

Dosimetric Comparison of Intensity-Modulated Radiation Therapy (IMRT) and Intensity-Modulated Proton Therapy (IMPT) for a Novel Oral Tongue Avoidance Concept in Low-Risk Squamous Cell Carcinoma of the Oral Tongue.

Purpose: After adequate surgical resection, early-stage oral tongue cancer patients can harbor a low risk of local recurrence but remain at risk of regional recurrence. Oral tongue avoidance during adjuvant radiation therapy is an attractive potential treatment strategy to mitigate treatment toxicity. We sought to quantify the dosimetric advantages of this approach and hypothesized that intensity-modulated proton therapy (IMPT) may further reduce organs at risk doses compared with intensity-modulated radiation therapy (IMRT). Materials and Methods: Five patients with oral tongue cancer treated with postoperative radiation therapy from August 2020 to September 2021 were retrospectively reviewed. Novel clinical target volume contours, excluding the oral tongue, were generated while maintaining coverage of bilateral at-risk lymph nodes. Comparison IMRT (X) and IMPT (PBT) plans were generated using standard treatment volumes (control) and avoidance volumes (study) (n = 4 plans/patient). Dosimetric variables for organs at risk were compared using the paired t test. Results: The prescribed dose was 60 Gy in 30 fractions. D95% clinical target volume coverage was similar between X and PBT plans for both control and study clinical target volumes. Comparing control with study plans, both X (58.9 Gy vs 38.3 Gy, P = .007) and PBT (60.2 Gy vs 26.1 Gy, P < .001) decreased the oral cavity dosemean. The pharyngeal constrictor dosemean was also reduced (P < .003). There was no difference between control and study plans for larynx (P = .19), parotid (P = .11), or mandible dose (P = .59). For study plans, PBT significantly reduced oral cavity dosemean (38.3 Gy vs 26.1 Gy, P = .007) and parotid dosemean (23.3 Gy vs 19.3 Gy, P = .03) compared with X. For control plans, there was no difference in oral cavity dosemean using PBT compared with X, but PBT did improve the parotid dosemean (26.6 Gy vs 19.7 Gy, P = .02). Conclusion: This study quantifies the feasibility and dosimetric advantages of oral tongue avoidance while still treating the at-risk lymph nodes for oral tongue cancer. The dosimetric difference between PBT and X was most prominent with an oral tongue-avoidance strategy.

Commissioning a 250 MeV research beamline for proton FLASH radiotherapy preclinical experiments.

BACKGROUND: The potential reduction of normal tissue toxicities during FLASH radiotherapy (FLASH-RT) has inspired many efforts to investigate its underlying mechanism and to translate it into the clinic. Such investigations require experimental platforms of FLASH-RT capabilities. PURPOSE: To commission and characterize a 250 MeV proton research beamline with a saturated nozzle monitor ionization chamber for proton FLASH-RT small animal experiments. METHODS: A 2D strip ionization chamber array (SICA) with high spatiotemporal resolution was used to measure spot dwell times under various beam currents and to quantify dose rates for various field sizes. An Advanced Markus chamber and a Faraday cup were irradiated with spot-scanned uniform fields and nozzle currents from 50 to 215 nA to investigate dose scaling relations. The SICA detector was set up upstream to establish a correlation between SICA signal and delivered dose at isocenter to serve as an in vivo dosimeter and monitor the delivered dose rate. Two off-the-shelf brass blocks were used as apertures to shape the dose laterally. Dose profiles in 2D were measured with an amorphous silicon detector array at a low current of 2 nA and validated with Gafchromic films EBT-XD at high currents of up to 215 nA. RESULTS: Spot dwell times become asymptotically constant as a function of the requested beam current at the nozzle of greater than 30 nA due to the saturation of monitor ionization chamber (MIC). With a saturated nozzle MIC, the delivered dose is always greater than the planned dose, but the desired dose can be achieved by scaling the MU of the field. The delivered doses exhibit excellent linearity with R 2 > 0.99 ${R^2} > 0.99$ with respect to MU, beam current, and the product of MU and beam current. If the total number of spots is less than 100 at a nozzle current of 215 nA, a field-averaged dose rate greater than 40 Gy/s can be achieved. The SICA-based in vivo dosimetry system achieved excellent estimates of the delivered dose with an average (maximum) deviation of 0.02 Gy (0.05 Gy) over a range of delivered doses from 3 to 44 Gy. Using brass aperture blocks reduced the 80%-20% penumbra by 64% from 7.55 to 2.75 mm. The 2D dose profiles measured by the Phoenix detector at 2 nA and the EBT-XD film at 215 nA showed great agreement, with a gamma passing rate of 95.99% using 1 mm/2% criterion. CONCLUSION: A 250 MeV proton research beamline was successfully commissioned and characterized. Challenges due to the saturated monitor ionization chamber were mitigated by scaling MU and using an in vivo dosimetry system. A simple aperture system was designed and validated to provide sharp dose fall-off for small animal experiments. This experience can serve as a foundation for other centers interested in implementing FLASH radiotherapy preclinical research, especially those equipped with a similar saturated MIC.