Inter- and intrafractional 4D dose accumulation for evaluating ΔNTCP robustness in lung cancer.

BACKGROUND AND PURPOSE: Model-based selection of proton therapy patients relies on a predefined reduction in normal tissue complication probability (NTCP) with respect to photon therapy. The decision is necessarily made based on the treatment plan, but NTCP can be affected when the delivered treatment deviates from the plan due to delivery inaccuracies. Especially for proton therapy of lung cancer, this can be important because of tissue density changes and, with pencil beam scanning, the interplay effect between the proton beam and breathing motion. MATERIALS AND METHODS: In this work, we verified whether the expected benefit of proton therapy is retained despite delivery inaccuracies by reconstructing the delivered treatment using log-file based dose reconstruction and inter- and intrafractional accumulation. Additionally, the importance of two uncertain parameters for treatment reconstruction, namely deformable image registration (DIR) algorithm and α/ß ratio, was assessed. RESULTS: The expected benefit or proton therapy was confirmed in 97% of all studied cases, despite regular differences up to 2 percent point (p.p.) NTCP between the delivered and planned treatments. The choice of DIR algorithm affected NTCP up to 1.6 p.p., an order of magnitude higher than the effect of α/ß ratio. CONCLUSION: For the patient population and treatment technique employed, the predicted clinical benefit for patients selected for proton therapy was confirmed for 97.0% percent of all cases, although the NTCP based proton selection was subject to 2 p.p. variations due to delivery inaccuracies.

Commissioning of a clinical pencil beam scanning proton therapy unit for ultra-high dose rates (FLASH).

PURPOSE: The purpose of this work was to provide a flexible platform for FLASH research with protons by adapting a former clinical pencil beam scanning gantry to irradiations with ultra-high dose rates. METHODS: PSI Gantry 1 treated patients until December 2018. We optimized the beamline parameters to transport the 250 MeV beam extracted from the PSI COMET accelerator to the treatment room, maximizing the transmission of beam intensity to the sample. We characterized a dose monitor on the gantry to ensure good control of the dose, delivered in spot-scanning mode. We characterized the beam for different dose rates and field sizes for transmission irradiations. We explored scanning possibilities in order to enable conformal irradiations or transmission irradiations of large targets (with transverse scanning). RESULTS: We achieved a transmission of 86% from the cyclotron to the treatment room. We reached a peak dose rate of 9000 Gy/s at 3 mm water equivalent depth, along the central axis of a single pencil beam. Field sizes of up to 5 × 5 mm2 were achieved for single-spot FLASH irradiations. Fast transverse scanning allowed to cover a field of 16 × 1.2 cm2 . With the use of a nozzle-mounted range shifter, we are able to span depths in water ranging from 19.6 to 37.9 cm. Various dose levels were delivered with precision within less than 1%. CONCLUSIONS: We have realized a proton FLASH irradiation setup able to investigate continuously a wide dose rate spectrum, from 1 to 9000 Gy/s in single-spot irradiation as well as in the pencil beam scanning mode. As such, we have developed a versatile test bench for FLASH research.

Clinical outcomes of head and neck adenoid cystic carcinoma patients treated with pencil beam-scanning proton therapy.

OBJECTIVE: The aim of this study was to evaluate the outcome of patients with head and neck adenoid cystic carcinoma (ACC) treated using pencil beam scanning proton therapy (PBS PT) at our institution. MATERIALS AND METHODS: Thirty-five patients who underwent treatment with PBS PT for ACC between 2001 and 2017 were included. Local control (LC), distant control (DC), progression-free survival (PFS), overall survival (OS) and their prognostic factors were evaluated. Adverse effects were prospectively assessed. RESULTS: The median patient follow-up was 30 months. Prior to PT, 26 patients (74.3%) underwent surgery with R0/R1/R2 outcome in 5, 13 and 8 cases, respectively. Nine patients (25.7%) presented with inoperable disease. The 2-year LC, DC, PFS and OS was 92.2%, 77.8%, 74.3% and 88.8%, respectively. LC was influenced by patient age (p = 0.002) with a significant difference between local and distant failure (median 61.3 vs. 42.3 years, p = 0.005). Tumor T stage was a significant risk factor for PFS (p = 0.045) and tumor prognostic group affected OS (p = 0.049). No significant survival advantage for operable vs. inoperable disease could be identified. The acute and late grade 3 toxicity rates were 14.3% and 6.1%, respectively. No acute or late grade 4/5 toxicities were observed. CONCLUSIONS: PBS PT is an effective and safe treatment for patients with head & neck ACC in both definitive and adjuvant setting. Distant metastases are the main pattern of failure. Age, tumor stage and clinical stage had a significant negative impact on LC, OS and PFS.

Long-Term Clinical Safety of High-Dose Proton Radiation Therapy Delivered With Pencil Beam Scanning Technique for Extracranial Chordomas and Chondrosarcomas in Adult Patients: Clinical Evidence of Spinal Cord Tolerance.

PURPOSE: To assess the radiation dose tolerance of the spinal cord by reviewing our institutional experience regarding the incidence of radiation-induced spinal cord toxicity after high-dose pencil beam scanning proton therapy (PBSPT). METHODS AND MATERIALS: Seventy-six patients (median age 53 years; range, 23-79 years) treated for spinal chordoma (n=55) or chondrosarcoma (n=21) met the following criteria and were retrospectively analyzed: PBSPT only, no reirradiation or concomitant chemotherapy, maximum dose (Dmax) to the spinal cord of ≥45 Gy(relative biological effectiveness [RBE]), ≥18 years of age, and follow-up of ≥12 months. The delivered dose was 59.4 to 75.2 Gy(RBE) [median 73.9 Gy(RBE)] delivered with conventional fractionation between 2000 and 2014. The Dmax, D2%, and V40-V60 of the surface (sSC) and center (cSC) of the spinal cord were recorded. Toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: Median follow-up was 65.5 months (range, 13-173 months). Patients received a mean Dmax and D2% to the sSC of 59.0 (median 58.7; range, 48.3-75.9) and 55.3 (median 52.7; range, 43.1-73.8) Gy(RBE), respectively. The corresponding values for the cSC were 52.3 (median 52.7; range, 32.3-73.3) and 51.1 (median 52.0; range, 25.3-73.1) Gy(RBE), respectively. Four patients (5%) developed acute radiation-induced neurotoxicity (grade [G] 1, n=1; G2, n=3). Twelve patients (16%) experienced late neurologic toxicities (G1, n=7; G2, n=4; G4, n=1). One patient with a history of pre-PBSPT symptomatic spinal cord compression redeveloped tetraplegia (G4) after receiving a Dmax of 57.8 Gy(RBE) to the sSC and 54.1 Gy(RBE) to the cSC. No significant correlation was found between sSC Dmax and D2%, cSC Dmax and D2%, or the length of CTV and toxicity. CONCLUSIONS: High-dose conformal PBSPT may be delivered safely in close proximity to the spinal cord with minimal neurotoxicity. Dose constraints of 64 Gy(RBE) as D2% for the sSC and 54 Gy(RBE) for the cSC seem appropriate for clinical use.

An Analysis of Plan Robustness for Esophageal Tumors: Comparing Volumetric Modulated Arc Therapy Plans and Spot Scanning Proton Planning.

PURPOSE: Planning studies to compare x-ray and proton techniques and to select the most suitable technique for each patient have been hampered by the nonequivalence of several aspects of treatment planning and delivery. A fair comparison should compare similarly advanced delivery techniques from current clinical practice and also assess the robustness of each technique. The present study therefore compared volumetric modulated arc therapy (VMAT) and single-field optimization (SFO) spot scanning proton therapy plans created using a simultaneous integrated boost (SIB) for dose escalation in midesophageal cancer and analyzed the effect of setup and range uncertainties on these plans. METHODS AND MATERIALS: For 21 patients, SIB plans with a physical dose prescription of 2 Gy or 2.5 Gy/fraction in 25 fractions to planning target volume (PTV)50Gy or PTV62.5Gy (primary tumor with 0.5 cm margins) were created and evaluated for robustness to random setup errors and proton range errors. Dose-volume metrics were compared for the optimal and uncertainty plans, with P<.05 (Wilcoxon) considered significant. RESULTS: SFO reduced the mean lung dose by 51.4% (range 35.1%-76.1%) and the mean heart dose by 40.9% (range 15.0%-57.4%) compared with VMAT. Proton plan robustness to a 3.5% range error was acceptable. For all patients, the clinical target volume D98 was 95.0% to 100.4% of the prescribed dose and gross tumor volume (GTV) D98 was 98.8% to 101%. Setup error robustness was patient anatomy dependent, and the potential minimum dose per fraction was always lower with SFO than with VMAT. The clinical target volume D98 was lower by 0.6% to 7.8% of the prescribed dose, and the GTV D98 was lower by 0.3% to 2.2% of the prescribed GTV dose. CONCLUSIONS: The SFO plans achieved significant sparing of normal tissue compared with the VMAT plans for midesophageal cancer. The target dose coverage in the SIB proton plans was less robust to random setup errors and might be unacceptable for certain patients. Robust optimization to ensure adequate target coverage of SIB proton plans might be beneficial.

Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation.

BACKGROUND AND PURPOSE: Non-homologous end-joining (NHEJ) and homologous recombination (HR) contribute to the repair of irradiation-induced DNA double-strand breaks (DSBs). We investigated the impact of the two major DSB repair machineries for cellular survival of human tumor cells in response to proton- and photon-irradiation. MATERIALS AND METHODS: DNA damage repair and cell survival were analyzed in wildtype, HR- and NHEJ-repair-compromised and pharmacologically DNA-PKcs-inhibited human tumor cells in response to clinically relevant, low-linear energy transfer proton- and 200-keV photon-irradiation. RESULTS: Pharmacological inhibition of DNA-PKcs strongly radiosensitized lung adenocarcinoma and glioblastoma cells to photon- but to a much lower extent to proton-irradiation. Enhanced radiosensitization correlated with strongly delayed repair kinetics with elevated amounts of γH2AX foci after photon-irradiation. Interestingly, we observed reduced phosphorylation of DNA-PKcs at Ser-2056 and Thr-2609 clusters after proton-irradiation compared to photon-irradiation. In contrast, A549 cells depleted of the RAD51 recombinase were markedly hypersensitive to proton-irradiation in comparison with control cells. Likewise, human BRCA2-deficient ovarian carcinoma cells were hypersensitive toward proton- in comparison with photon-irradiation. CONCLUSION: A differential DNA damage response with enhanced susceptibility of HR-deficient tumor cells to proton-irradiation and increased sensitivity of photon-irradiated tumor cells to NHEJ inhibitors were demonstrated.

Proton therapy for malignant pleural mesothelioma after extrapleural pleuropneumonectomy.

PURPOSE: To perform comparative planning for intensity-modulated radiotherapy (IMRT) and proton therapy (PT) for malignant pleural mesothelioma after radical surgery. METHODS AND MATERIALS: Eight patients treated with IMRT after extrapleural pleuropneumonectomy (EPP) were replanned for PT, comparing dose homogeneity, target volume coverage, and mean and maximal dose to organs at risk. Feasibility of PT was evaluated regarding the dose distribution with respect to air cavities after EPP. RESULTS: Dose coverage and dose homogeneity of the planning target volume (PTV) were significantly better for PT than for IMRT regarding the volume covered by >95% (V95) for the high-dose PTV. The mean dose to the contralateral kidney, ipsilateral kidney, contralateral lung, liver, and heart and spinal cord dose were significantly reduced with PT compared with IMRT. After EPP, air cavities were common (range, 0-850 cm(3)), decreasing from 0 to 18.5 cm(3)/day. In 2 patients, air cavity changes during RT decreased the generalized equivalent uniform dose (gEUD) in the case of using an a value of < - 10 to the PTV2 to <2 Gy in the presence of changing cavities for PT, and to 40 Gy for IMRT. Small changes were observed for gEUD of PTV1 because PTV1 was reached by the beams before air. CONCLUSION: Both PT and IMRT achieved good target coverage and dose homogeneity. Proton therapy accomplished additional dose sparing of most organs at risk compared with IMRT. Proton therapy dose distributions were more susceptible to changing air cavities, emphasizing the need for adaptive RT and replanning.

Proton spot scanning radiotherapy of spontaneous canine tumors.

Thirty dogs with spontaneous tumors were irradiated with proton therapy using a novel spot scanning technique to evaluate the safety and efficacy of the system, and to study the acute and late radiation reactions. Nasal tumors, soft tissue sarcomas, and miscellaneous tumors of the head were treated with a median total dose of 52.5 Gy given in 3.5 Gy fractions. Acute effects, late effects, tumor response, and outcome were analyzed. No unexpected radiation reactions were seen, however two dogs did develop in-field osteosarcoma, and one dog developed in-field bone necrosis. Complete response to therapy was seen in 40% (12/30), partial response in 47% (14/30), and no response in 13% (4/30). Median survival for all dogs was 385 days (range of 14-4583 days). Dogs with nasal cavity tumors had a median survival of 385 days (range of 131-1851 days) and dogs with soft tissue sarcomas had a median survival time of 612 days (range of 65-4588 days). Treatment outcome was similar to historical controls. This new proton spot scanning technique proved to be safe and reliable.