FLASH Radiotherapy Using Single-Energy Proton PBS Transmission Beams for Hypofractionation Liver Cancer: Dose and Dose Rate Quantification

PurposeThis work aims to study the dose and ultra-high-dose rate characteristics of transmission proton pencil beam scanning (PBS) FLASH radiotherapy (RT) for hypofractionation liver cancer based on the parameters of a commercially available proton system operating under FLASH mode.Methods and MaterialsAn in-house treatment planning software (TPS) was developed to perform intensity-modulated proton therapy (IMPT) FLASH-RT planning. Single-energy transmission proton PBS plans of 4.5 Gy × 15 fractions were optimized for seven consecutive hepatocellular carcinoma patients, using 2 and 5 fields combined with 1) the minimum MU/spot chosen between 100 and 400, and minimum spot time (MST) of 2 ms, and 2) the minimum MU/spot of 100, and MST of 0.5 ms, based upon considerations in target uniformities, OAR dose constraints, and OAR FLASH dose rate coverage. Then, the 3D average dose rate distribution was calculated. The dose metrics for the mean dose of Liver-GTV and other major OARs were characterized to evaluate the dose quality for the different combinations of field numbers and minimum spot times compared to that of conventional IMPT plans. Dose rate quality was evaluated using 40 Gy/s volume coverage (V40Gy/s).ResultsAll plans achieved favorable and comparable target uniformities, and target uniformity improved as the number of fields increased. For OARs, no significant dose differences were observed between plans of different field numbers and the same MST. For plans using shorter MST and the same field numbers, better sparing was generally observed in most OARs and was statistically significant for the chest wall. However, the FLASH dose rate coverage V40Gy/s was increased by 20% for 2-field plans compared to 5-field plans in most OARs with 2-ms MST, which was less evident in the 0.5-ms cases. For 2-field plans, dose metrics and V40Gy/s of select OARs have large variations due to the beam angle selection and variable distances to the targets. The transmission plans generally yielded inferior dosimetric quality to the conventional IMPT plans.ConclusionThis is the first attempt to assess liver FLASH treatment planning and demonstrates that it is challenging for hypofractionation with smaller fractional doses (4.5 Gy/fraction). Using fewer fields can allow higher minimum MU/spot, resulting in higher OAR FLASH dose rate coverages while achieving similar plan quality compared to plans with more fields. Shorter MST can result in better plan quality and comparable or even better FLASH dose rate coverage.

Post-Irradiation Sinus Mucosa Disease in Nasopharyngeal Carcinoma Patients Treated with Intensity-Modulated Proton Therapy

In the past decade, patients with nasopharyngeal cancer (NPC) have been deemed candidates for proton radiotherapy, due to the large and comprehensive target volumes and the necessity for the retention of the surrounding healthy tissues. In this study, we aimed to compare the incidence and severity of post-irradiation sinusitis by detecting sinus mucosa diseases (SMDs) via the magnetic resonance imaging (MRI) of patients with NPC after intensity-modulated proton therapy (IMPT) and volume-modulated arc therapy (VMAT). A total of 53 patients in the IMPT group and 54 patients in the VMAT group were enrolled in this study. There were significantly lower endoscopic scores and Lund–Mackay staging scores determined from MRI scans in the IMPT group during different follow-up periods. For the most vulnerable sinuses, the incidence and severity of SMD were the highest during the third post-radiotherapy month in both groups. These decreased steadily, and there was no significant increase in the incidence and severity of SMD during the second post-radiotherapy year in the IMPT group. Our data show that NPC patients with IMPT have a significantly lower incidence and decreased severity of SMD than those with VMAT. A better and faster recovery of sinonasal function after radiotherapy in the IMPT group was also observed.

Pencil Beam Scanning (PBS) Intensity-Modulated Proton Therapy (IMPT) Chemoradiotherapy for Anal Canal Cancer—Single Institution Experience

Background: A favourable dose distribution has been described for proton beam therapy (PBT) of anal cancer in dosimetric studies. The relationship between dosimetric parameters in bone marrow and haematologic toxicity, treatment interruptions, and treatment efficacy has also been documented. There are only few references on clinical results of PBT for anal cancer. The primary objective of the retrospective study was to assess the efficacy of pencil beam scanning intensity-modulated proton therapy (PBS IMPT) in the definitive chemoradiotherapy of anal cancer. Secondary objectives were established to identify the risks of acute chronic toxicity risks and to assess colostomy rates. Materials and methods: Patients were treated for biopsy-proven squamous cell cancer (SCC) of the anus at initial or advanced stages. Eligible patients received PBS IMPT at a single institution. Treatment was administered in two volumes: 1—tumour with margins plus involved lymph nodes; 2—regional lymph node groups: perirectal (mesorectal), obturatory, inguinal, internal, external, and common iliac. The total doses of 57.5 GyE and 45 GyE, respectively, were administered in volumes 1 and 2 in 25 fractions, 5 fractions per week, respectively (a simultaneous integrated boost). Concomitant chemotherapy cisplatinum (CDDP) plus 5-FU or CDDP plus capecitabine was administered as per protocol. The treatment effect was assessed using DRE (digital rectal examination) and MRI (magnetic resonance imaging) within the follow-up period. Toxicity was scaled using CTCAE version 4.0 criteria. Results: 39 of 41 patients treated during the period of February 2014–August 2021 were eligible for analysis. All patients completed treatment, 76.9% without interruption. The median treatment time was 35 days (32–35). The median follow-up period was 30 months, 34 patients are alive to-date, 5 patients died prior to the date of analysis, and 2 deaths were unrelated to the primary disease. The 2-year overall survival, relapse-free survival, and colostomy-free survival were 94.2%, 93.8%, and 91.0%, respectively. Complete regression was achieved in 36 patients (92.3%), partial regression was achieved in 2 (5.1%), and immediate progression at end of treatment occurred in 1 patient (2.6%). Salvage resection was indicated for two patients in partial regression and due to severe chronic dermatologic toxicity. The grade 3 and 4 haematological toxicity rates were 7.7% and 5.1%, respectively. The most frequent non-haematological acute toxicities of grade 3–4 observed were dermatitis (23.1%), diarrhoea (7.7%), and dehydration (7.7%). Chronic toxicity emerged predominantly as skin atrophy/ulceration grade 2 (26.5%) and grade 3–4 (5.8%), and radiation proctitis grade 2 (38.2%) and grade 3 (2.9%). Discussion, conclusions: This single-institution study showed the high efficacy of PBS IMPT, achieving a high rate of complete regression. The haematological acute toxicity of grade 3–4 remained low; however, the impact of altered chemotherapy (CDDP instead of mitomycin C) remains unclear. The incidence of other acute toxicities shares similarity with photon therapy investigated in large studies. The acute toxicity completely resolved in all patients, had no lethal outcomes, and never resulted in the necessity for colostomy. By contrast, it was chronic toxicity, skin ulceration, perirectal fistulation, and fibrosis that resulted in salvage surgery and/or the need for a colostomy. A challenging question remains: to what extent can PBT prevent chronic toxicity? Longer follow-up remains necessary.

Ultra-Hypofractionated Proton Therapy in Localized Prostate Cancer: Passive Scattering versus Intensity-Modulated Proton Therapy

Few studies have directly compared passive scattering (PS) to intensity-modulated proton therapy (IMPT) in the delivery of ultra-hypofractionated proton beams to the localized prostate cancer (PCa). In this preliminary study involving five patients previously treated with CyberKnife, treatment plans were created for PS and IMPT (36.25 CGE in five fractions with two opposing fields) to compare the dosimetric parameters to the planning target volume (PTV) and organs-at-risk (OAR: rectum, bladder, femoral heads). Both plans met the acceptance criteria. Significant differences were observed in the minimum and maximum doses to the PTV. The mean dose to the PTV was lower for PS (35.62 ± 0.26 vs. 37.18 ± 0.14; p = 0.002). Target coverage (D98%) was better for IMPT (96.79% vs. 99.10%; p = 0.004). IMPT resulted in significantly lower mean doses to the rectum (16.75 CGE vs. 6.88 CGE; p = 0.004) and bladder (17.69 CGE vs. 5.98 CGE p = 0.002). High dose to the rectum (V36.25 CGE) were lower with PS, but not significantly opposite to high dose to the bladder. No significant differences were observed in mean conformity index values, with a non-significant trend towards higher mean homogeneity index values for PS. Non-significant differences in the gamma index for both fields were observed. These findings suggest that both PS and IMPT ultra-hypofractionated proton therapy for PCa are highly precise, offering good target coverage and sparing of normal tissues and OARs.

RADT-35. CHANGE IN HIPPOCAMPAL VOLUME AS A FUNCTION OF RADIATION DOSE: RESULTS FROM A PROSPECTIVE TRIAL WITH STANDARDIZED IMAGING AND MORPHOMETRIC EVALUATION

PURPOSE/OBJECTIVES MRIs in pediatric and adult brain tumor patients (Age< 35) were prospectively collected at baseline and during follow-up to measure volumetric changes in multiple brain substructures with neurocognitive, laboratory, and quality-of-life assessments. In this planned interim analysis, we model early outcomes for change in hippocampal volume at 6 months following radiotherapy. MATERIALS AND METHODS As of 5/15/2021, 50 patients enrolled on this prospective study and 41 completed 6-month post-treatment assessments after fractionated intensity-modulated proton therapy. Left and right hippocampus volumes were independently measured on T1 sagittal precontrast MRI at baseline and 6-months after radiotherapy using both automated software and physician-delineated contours. The relationship between mean hippocampus dose and change in volume was assessed by Pearson’s correlation coefficient. A linear mixed-effects model was applied to evaluate other predictors associated with change in hippocampal volume, assuming random effects of subjects. RESULTS Mean hippocampus dose was strongly correlated with change in hippocampal volume at 6 months following radiotherapy (r=−0.727, 95% CI [-0.820,-0.596], p< 0.001). Changes in hippocampal volumes over time were similar between software and physician contours. Hippocampal volume was significantly reduced for mean doses ≥10 Gy (mean Δ -10.8% ± 5.5%, p< 0.001), while no significant volume change was observed with mean doses < 10 Gy (mean Δ +0.7% ± 3.9%). In the mixed-effects model, only mean hippocampus dose was significantly associated with hippocampal volume change (p< 0.001). The final model predicted a -3.4% change in hippocampal volume for every 10 Gy increase in mean dose. CONCLUSIONS Change in hippocampal volume was correlated with hippocampus mean dose at 6 months following radiotherapy. Future analyses will assess volume change in the hippocampus and other brain substructures over time as a function of radiation dose and correlate with measured neurocognitive and other effects.