Accurate machine-specific reference and small-field dosimetry for a self-shielded neuro-radiosurgical system.

BACKGROUND: The newly available ZAP-X stereotactic radiosurgical system is designed for the treatment of intracranial lesions, with several unique features that include a self-shielding, gyroscopic gantry, wheel collimation, non-orthogonal kV imaging, short source-axis distance, and low-energy megavoltage beam. Systematic characterization of its radiation as well as other properties is imperative to ensure its safe and effective clinical application. PURPOSE: To accurately determine the radiation output of the ZAP-X with a special focus on the smaller diameter cones and an aim to provide useful recommendations on quantification of small field dosimetry. METHODS: Six different types of detectors were used to measure relative output factors at field sizes ranging from 4 to 25 mm, including the PTW microSilicon and microdiamond diodes, Exradin W2 plastic scintillator, Exradin A16 and A1SL ionization chambers, and the alanine dosimeter. The 25 mm cone served as the reference field size. Absolute dose was determined with both TG-51-based dosimetry using a calibrated PTW Semiflex ion chamber and measurements using alanine dosimeters. RESULTS: The average radiation output factors (maximum deviation from the average) measured with the microDiamond, microSilicon, and W2 detectors were: for the 4 mm cone, 0.741 (1.0%); for the 5 mm cone: 0.817 (1.0%); for the 7.5 mm cone: 0.908 (1.0%); for the 10 mm cone: 0.946 (0.4%); for the 12.5 mm cone: 0.964 (0.2%); for the 15 mm cone: 0.976 (0.1%); for the 20 mm cone: 0.990 (0.1%). For field sizes larger than 10 mm, the A1SL and A16 micro-chambers also yielded consistent output factors within 1.5% of those obtained using the microSilicon, microdiamond, and W2 detectors. The absolute dose measurement obtained with alanine was within 1.2%, consistent with combined uncertainties, compared to the PTW Semiflex chamber for the 25 mm reference cone. CONCLUSION: For field sizes less than 10 mm, the microSilicon diode, microDiamond detector, and W2 scintillator are suitable devices for accurate small field dosimetry of the ZAP-X system. For larger fields, the A1SL and A16 micro-chambers can also be used. Furthermore, alanine dosimetry can be an accurate verification of reference and absolute dose typically measured with ion chambers. Use of multiple suitable detectors and uncertainty analyses were recommended for reliable determination of small field radiation outputs.

Proton induced DNA double strand breaks at the Bragg peak: Evidence of enhanced LET effect.

Purpose: To investigate DNA double strand breaks (DSBs) induced by therapeutic proton beams in plateau and Bragg peak to demonstrate DSB induction due to the higher LET in the Bragg peak. Materials and Methods: pUC19 plasmid DNA samples were irradiated to doses of 1000 and 3000 Gy on a Mevion S250i proton system with a monoenergetic, 110 MeV, proton beam at depths of 2 and 9.4 cm, corresponding to a position on the plateau and distal Bragg peak of the beam, respectively. The irradiated DNA samples were imaged by atomic force microscopy for visualization of individual DNA molecules, either broken or intact, and quantification of the DNA fragment length distributions for each of the irradiated samples. Percentage of the broken DNA and average number of DSBs per DNA molecule were obtained. Results: Compared to irradiation effects in the plateau region, DNA irradiated at the Bragg peak sustained more breakage at the same dose, yielding more short DNA fragments and higher numbers of DSB per DNA molecule. Conclusion: The higher LET of proton beams at the Bragg peak results in more densely distributed DNA DSBs, which supports an underlying mechanism for the increased cell killing by protons at the Bragg peak.

Prostate Cancer Treatment with Pencil Beam Proton Therapy Using Rectal Spacers sans Endorectal Balloons.

Purpose: Proton beam radiotherapy (PBT) has been used for the definitive treatment of localized prostate cancer with low rates of high-grade toxicity and excellent patient-reported quality-of-life metrics. Technological advances such as pencil beam scanning (PBS), Monte Carlo dose calculations, and polyethylene glycol gel rectal spacers have optimized prostate proton therapy. Here, we report the early clinical outcomes of patients treated for localized prostate cancer using modern PBS-PBT with hydrogel rectal spacing and fiducial tracking without the use of endorectal balloons. Materials and Methods: This is a single institutional review of consecutive patients treated with histologically confirmed localized prostate cancer. Prior to treatment, all patients underwent placement of fiducials into the prostate and insertion of a hydrogel rectal spacer. Patients were typically given a prescription dose of 7920 cGy at 180 cGy per fraction using a Monte Carlo dose calculation algorithm. Acute and late toxicity were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Biochemical failure was defined using the Phoenix definition. Results: From July 2018 to April 2020, 33 patients were treated (median age, 75 years). No severe acute toxicities were observed. The most common acute toxicity was urinary frequency. With a median follow-up of 18 months, there were no high-grade genitourinary late toxicities; however, one grade 3 gastrointestinal toxicity was observed. Late erectile dysfunction was common. One treatment failure was observed at 21 months in a patient treated for high-risk prostate cancer. Conclusion: Early clinical outcomes of patients treated with PBS-PBT using Monte Carlo-based planning, fiducial placement, and rectal spacers sans endorectal balloons demonstrate minimal treatment-related toxicity with good oncologic outcomes. Rectal spacer stabilization without the use of endorectal balloons is feasible for the use of PBS-PBT.

18Oxygen Substituted Nucleosides Combined with Proton Beam Therapy: Therapeutic Transmutation In Vitro.

PURPOSE: Proton therapy precisely delivers radiation to cancers to cause damaging strand breaks to cellular DNA, kill malignant cells, and stop tumor growth. Therapeutic protons also generate short-lived activated nuclei of carbon, oxygen, and nitrogen atoms in patients as a result of atomic transmutations that are imaged by positron emission tomography (PET). We hypothesized that the transition of 18O to 18F in an 18O-substituted nucleoside irradiated with therapeutic protons may result in the potential for combined diagnosis and treatment for cancer with proton therapy. MATERIALS AND METHODS: Reported here is a feasibility study with a therapeutic proton beam used to irradiate H2 18O to a dose of 10 Gy produced by an 85 MeV pristine Bragg peak. PET imaging initiated >45 minutes later showed an 18F decay signal with T1/2 of ∼111 minutes. RESULTS: The 18O to 18F transmutation effect on cell survival was tested by exposing SQ20B squamous carcinoma cells to physiologic 18O-thymidine concentrations of 5 µM for 48 hours followed by 1- to 9-Gy graded doses of proton radiation given 24 hours later. Survival analyses show radiation sensitization with a dose modification factor (DMF) of 1.2. CONCLUSIONS: These data support the idea of therapeutic transmutation in vitro as a biochemical consequence of proton activation of 18O to 18F in substituted thymidine enabling proton radiation enhancement in a cancer cell. 18O-substituted molecules that incorporate into cancer targets may hold promise for improving the therapeutic window of protons and can be evaluated further for postproton therapy PET imaging.

Early Experience of the First Single-Room Gantry Mounted Active Scanning Proton Therapy System at an Integrated Cancer Center.

Introduction: Review the early experience with a single-room gantry mounted active scanning proton therapy system. Material and Methods: All patients treated with proton beam radiotherapy (PBT) were enrolled in an institutional review board-approved patient registry. Proton beam radiotherapy was delivered with a 250 MeV gantry mounted synchrocyclotron in a single-room integrated facility within the pre-existing cancer center. Demographic data, cancer diagnoses, treatment technique, and geographic patterns were obtained for all patients. Treatment plans were evaluated for mixed modality therapy. Insurance approval data was collected for all patients treated with PBT. Results: A total of 132 patients were treated with PBT between March 2018 and June 2019. The most common oncologic subsites treated included the central nervous system (22%), gastrointestinal tract (20%), and genitourinary tract (20%). The most common histologies treated included prostate adenocarcinoma (19%), non-small cell lung cancer (10%), primary CNS gliomas (8%), and esophageal cancer (8%). Rationale for PBT treatment included limitation of dose to adjacent critical organs at risk (67%), reirradiation (19%), and patient comorbidities (11%). Patients received at least one x-ray fraction delivered as prescribed (36%) or less commonly due to unplanned machine downtime (34%). Concurrent systemic therapy was administered to 57 patients (43%). Twenty-six patients (20%) were initially denied insurance coverage and required peer-to-peers (65%), written appeals (12%), secondary insurance approval (12%), and comparison x-ray to proton plans (8%) for subsequent approval. Proton beam radiotherapy approval required a median of 17 days from insurance submission. Discussion: Incorporation of PBT into our existing cancer center allowed for multidisciplinary oncologic treatment of a diverse population of patients. Insurance coverage for PBT presents as a significant hurdle and improvements are needed to provide more timely access to necessary oncologic care.

Cross-institutional knowledge-based planning (KBP) implementation and its performance comparison to Auto-Planning Engine (APE).

BACKGROUND AND PURPOSE: To investigate (1) whether a plan library established at one institution can be applied for another institution's knowledge-based planning (KBP); (2) the performance of cross-institutional KBP compared to Auto-Planning Engine (APE). MATERIAL AND METHODS: Radboud University Medical Center (RUMC) provided 35 oropharyngeal cancer patients (68Gy to PTV68 and 50.3Gy to PTV50.3) with clinically-delivered and comparative APE plans. The Johns Hopkins University (JHU) contributed a three-dose-level plan library consisting of 179 clinically-delivered plans. MedStar Georgetown University Hospital (MGUH) contributed a KBP approach employing overlap-volume histogram (OVH-KBP), where the JHU library was used for guiding RUMC patients' KBP. Since clinical protocols adopted at RUMC and JHU are different and both approaches require protocol-specific planning parameters as initial input, 10 randomly selected patients from RUMC were set aside for deriving them. The finalized parameters were applied to the remaining 25 patients for OVH-KBP and APE plan generation. A Wilcoxon rank-sum test was used for statistical comparison. RESULTS: PTV68 and PTV50.3's V95 in OVH-KBP and APE were similar (p>0.36). Cord's D0.1 cc in OVH-KBP was reduced by 5.1Gy (p=0.0001); doses to other organs were similar (p>0.2). CONCLUSION: APE and OVH-KBP's plan quality is comparable. Institutional-protocol differences can be addressed to allow cross-institutional library sharing.

Short DNA Fragments Are a Hallmark of Heavy Charged-Particle Irradiation and May Underlie Their Greater Therapeutic Efficacy.

Growing interest in proton and heavy ion therapy has reinvigorated research into the fundamental biological mechanisms underlying the therapeutic efficacy of charged-particle radiation. To improve our understanding of the greater biological effectiveness of high-LET radiations, we have investigated DNA double-strand breaks (DSBs) following exposure of plasmid DNA to low-LET Co-60 gamma photon and electron irradiation and to high-LET Beryllium and Argon ions with atomic force microscopy. The sizes of DNA fragments following radiation exposure were individually measured to construct fragment size distributions from which the DSB per DNA molecule and DSB spatial distributions were derived. We report that heavy charged particles induce a significantly larger proportion of short DNA fragments in irradiated DNA molecules, reflecting densely and clustered damage patterns of high-LET energy depositions. We attribute the enhanced short DNA fragmentation following high-LET radiations as an important determinant of the observed, enhanced biological effectiveness of high-LET irradiations.

Automated Extraction of Dose/Volume Statistics for Radiotherapy-Treatment-Plan Evaluation in Clinical-Trial Quality Assurance.

Radiotherapy clinical-trial quality assurance is a crucial yet challenging process. This note presents a tool that automatically extracts dose/volume statistics for determining dosimetry compliance review with improved efficiency and accuracy. A major objective of this study is to develop an automated solution for clinical-trial radiotherapy dosimetry review.

Multisession Radiosurgery for Hearing Preservation.

Clinically relevant dose-tolerance limits with reliable estimates of risk in 1-5 fractions for cochlea are still unknown. Timmerman׳s limits from the October 2008 issue of Seminars in Radiation Oncology have served as the basis for clinical practice, augmented by updated constraints in TG-101 and QUANTEC, but the corresponding estimates of risk have not yet been well-reported. A total of 37 acoustic neuroma CyberKnife cases from Medstar Georgetown University Hospital treated in 3 or 5 fractions were combined with single-fraction Gamma Knife data from the 69 cases in Timmer 2009 to form an aggregate dataset of 106 cochlea cases treated in 1-5 fractions. Probit dose-response modeling was performed in the DVH Evaluator software to estimate normal tissue complication probability. QUANTEC recommends keeping single-fraction maximum dose to the cochlea less than 14Gy to maintain less than 25% risk of serviceable hearing loss, and our 17.9% risk estimate for 14Gy in 1 fraction is within their predicted range. In 5 fractions, our estimate of the Timmerman 27.5Gy maximum cochlea dose limit was 17.4%. For cases in which lower risk is required, the Timmerman 12Gy in 1 fraction and the TG-101 limit of 25Gy in 5 fractions had an estimated risk level of 11.8% and 13.8%, respectively. High-risk and low-risk dose tolerance with risk estimates in 1-5 fractions are all presented.

DNA studies using atomic force microscopy: capabilities for measurement of short DNA fragments.

Short DNA fragments, resulting from ionizing radiation induced DNA double strand breaks (DSBs), or released from cells as a result of physiological processes and circulating in the blood stream, may play important roles in cellular function and potentially in disease diagnosis and early intervention. The size distribution of DNA fragments contribute to knowledge of underlining biological processes. Traditional techniques used in radiation biology for DNA fragment size measurements lack the resolution to quantify short DNA fragments. For the measurement of cell-free circulating DNA (ccfDNA), real time quantitative Polymerase Chain Reaction (q-PCR) provides quantification of DNA fragment sizes, concentration and specific gene mutation. A complementary approach, the imaging-based technique using Atomic Force Microscopy (AFM) provides direct visualization and measurement of individual DNA fragments. In this review, we summarize and discuss the application of AFM-based measurements of DNA fragment sizes. Imaging of broken plasmid DNA, as a result of exposure to ionizing radiation, as well as ccfDNA in clinical specimens offer an innovative approach for studies of short DNA fragments and their biological functions.

Improved robotic stereotactic body radiation therapy plan quality and planning efficacy for organ-confined prostate cancer utilizing overlap-volume histogram-driven planning methodology.

BACKGROUND AND PURPOSE: This study is to determine if the overlap-volume histogram (OVH)-driven planning methodology can be adapted to robotic SBRT (CyberKnife Robotic Radiosurgery System) to further minimize the bladder and rectal doses achieved in plans manually-created by clinical planners. METHODS AND MATERIALS: A database containing clinically-delivered, robotic SBRT plans (7.25 Gy/fraction in 36.25 Gy) of 425 patients with localized prostate cancer was used as a cohort to establish an organ's distance-to-dose model. The OVH-driven planning methodology was refined by adding the PTV volume factor to counter the target's dose fall-off effect and incorporated into Multiplan to automate SBRT planning. For validation, automated plans (APs) for 12 new patients were generated, and their achieved dose/volume values were compared to the corresponding manually-created, clinically-delivered plans (CPs). A two-sided, Wilcoxon rank-sum test was used for statistical comparison with a significance level of p<0.05. RESULTS: PTV's V(36.25 Gy) was comparable: 95.6% in CPs comparing to 95.1% in APs (p=0.2). On average, the refined approach lowered V(18.12 Gy) to the bladder and rectum by 8.2% (p<0.05) and 6.4% (p=0.14). A physician confirmed APs were clinically acceptable. CONCLUSIONS: The improvements in APs could further reduce toxicities observed in SBRT for organ-confined prostate cancer.

Significant disparity in base and sugar damage in DNA resulting from neutron and electron irradiation.

In this study, a comparison of the effects of neutron and electron irradiation of aqueous DNA solutions was investigated to characterize potential neutron signatures in DNA damage induction. Ionizing radiation generates numerous lesions in DNA, including base and sugar lesions, lesions involving base-sugar combinations (e.g. 8,5'-cyclopurine-2'-deoxynucleosides) and DNA-protein cross-links, as well as single- and double-strand breaks and clustered damage. The characteristics of damage depend on the linear energy transfer (LET) of the incident radiation. Here we investigated DNA damage using aqueous DNA solutions in 10 mmol/l phosphate buffer from 0-80 Gy by low-LET electrons (10 Gy/min) and the specific high-LET (∼0.16 Gy/h) neutrons formed by spontaneous (252)Cf decay fissions. 8-hydroxy-2'-deoxyguanosine (8-OH-dG), (5'R)-8,5'-cyclo-2'-deoxyadenosine (R-cdA) and (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA) were quantified using liquid chromatography-isotope-dilution tandem mass spectrometry to demonstrate a linear dose dependence for induction of 8-OH-dG by both types of radiation, although neutron irradiation was ∼50% less effective at a given dose compared with electron irradiation. Electron irradiation resulted in an exponential increase in S-cdA and R-cdA with dose, whereas neutron irradiation induced substantially less damage and the amount of damage increased only gradually with dose. Addition of 30 mmol/l 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), a free radical scavenger, to the DNA solution before irradiation reduced lesion induction to background levels for both types of radiation. These results provide insight into the mechanisms of DNA damage by high-LET (252)Cf decay neutrons and low-LET electrons, leading to enhanced understanding of the potential biological effects of these types of irradiation.

Multi-marker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer.

Development of a Q-PCR-based assay for the high-performance analysis of circulating cell-free DNA (ccfDNA) requires good knowledge of its structure and size. In this work, we present the first visual determination of ccfDNA by Atomic Force Microscopy (AFM) on plasma samples from colorectal cancer (CRC) patients and healthy donors. In addition to the examination of fragment size distribution profile as performed by Q-PCR, this analysis confirms that ccfDNA is highly fragmented and that more than 80% of ccfDNA fragments in CRC plasma are below 145 bp. We adapted an Allele-Specific Blocker (ASB) Q-PCR to small ccfDNA fragments to determine simultaneously the total ccfDNA concentration, the presence of point mutation, the proportion of mutated allele, and a ccfDNA integrity index. The data validated analytically these four parameters in 124 CRC clinical samples and 71 healthy individuals. The multi-marker method, termed Intplex, enables sensitive and specific non-invasive analysis of tumor ccfDNA, which has great potential in terms of cost, quality control, and easy implementation in every clinical center laboratory.

Using overlap volume histogram and IMRT plan data to guide and automate VMAT planning: a head-and-neck case study.

PURPOSE: To investigate whether an overlap volume histogram (OVH)-driven planning application using an intensity-modulated radiation therapy (IMRT) database can guide and automate volumetric-modulated arc therapy (VMAT) planning for head-and-neck cancer. METHODS: Based on comparable head-and-neck dosimetric results between planner-generated VMAT and IMRT plans, an inhouse developed, OVH-driven automated planning application containing a database of prior clinical head-and-neck IMRT plans is built into Pinnacle(3) SmartArc for VMAT planning. Double-arc VMAT plans of four oropharynx, four nasopharynx, and four larynx patients are generated and compared with corresponding clinical IMRT plans. RESULTS: Each VMAT plan is automatically generated in two optimization rounds, while the average number of optimization rounds in generating a clinical IMRT plan is 43. In VMAT plans, statistical superiority (p < 0.01) in sparing of the cord+4 mm, brainstem, brachial plexus, larynx, and inner ear is observed with a slight degradation in low-dose-level planning target volume (PTV) coverage. On average, D(0.1 cc) to the cord+4 mm, brainstem and brachial plexus is reduced by 3.7, 4.9, and 1.6 Gy, respectively; V(50 Gy) to the larynx is reduced by 5.3%; mean dose to the inner ear is reduced by 4.4 Gy; V(95) of low-dose-level PTV coverage is reduced by 0.3% with p = 0.25. CONCLUSIONS: IMRT-data-driven VMAT planning offers a potential method for generating VMAT plans that are comparable to IMRT plans in terms of dosimetric quality.

Fully automated simultaneous integrated boosted-intensity modulated radiation therapy treatment planning is feasible for head-and-neck cancer: a prospective clinical study.

PURPOSE: To prospectively determine whether overlap volume histogram (OVH)-driven, automated simultaneous integrated boosted (SIB)-intensity-modulated radiation therapy (IMRT) treatment planning for head-and-neck cancer can be implemented in clinics. METHODS AND MATERIALS: A prospective study was designed to compare fully automated plans (APs) created by an OVH-driven, automated planning application with clinical plans (CPs) created by dosimetrists in a 3-dose-level (70 Gy, 63 Gy, and 58.1 Gy), head-and-neck SIB-IMRT planning. Because primary organ sparing (cord, brain, brainstem, mandible, and optic nerve/chiasm) always received the highest priority in clinical planning, the study aimed to show the noninferiority of APs with respect to PTV coverage and secondary organ sparing (parotid, brachial plexus, esophagus, larynx, inner ear, and oral mucosa). The sample size was determined a priori by a superiority hypothesis test that had 85% power to detect a 4% dose decrease in secondary organ sparing with a 2-sided alpha level of 0.05. A generalized estimating equation (GEE) regression model was used for statistical comparison. RESULTS: Forty consecutive patients were accrued from July to December 2010. GEE analysis indicated that in APs, overall average dose to the secondary organs was reduced by 1.16 (95% CI = 0.09-2.33) with P=.04, overall average PTV coverage was increased by 0.26% (95% CI = 0.06-0.47) with P=.02 and overall average dose to the primary organs was reduced by 1.14 Gy (95% CI = 0.45-1.8) with P=.004. A physician determined that all APs could be delivered to patients, and APs were clinically superior in 27 of 40 cases. CONCLUSIONS: The application can be implemented in clinics as a fast, reliable, and consistent way of generating plans that need only minor adjustments to meet specific clinical needs.

Radiation-generated short DNA fragments may perturb non-homologous end-joining and induce genomic instability.

Cells exposed to densely ionizing radiation (high-LET) experience more severe biological damage than do cells exposed to sparsely ionizing radiation (low-LET). The prevailing hypothesis is that high-LET radiations induce DNA double strand-breaks (DSB) that are more complex and clustered, and are thereby more challenging to repair. Here, we present experimental data obtained by atomic force microscopy imaging, DNA-dependent protein kinase (DNA-PK) activity determination, DNA ligation assays, and genomic studies to suggest that short DNA fragments are important products of radiation-induced DNA lesions, and that the lengths of DNA fragments may be significant in the cellular responses to ionizing radiation. We propose the presence of a subset of short DNA fragments that may affect cell survival and genetic stability following exposure to ionizing radiation, and that the enhanced biological effects of high-LET radiation may be explained, in part, by the production of increased quantities of short DNA fragments.

Spatial distribution of radiation-induced double-strand breaks in plasmid DNA as resolved by atomic force microscopy.

Atomic force microscopy (AFM) has been used to directly visualize, size and compare the DNA fragments resulting from exposure to low- and high-LET radiation. Double-stranded pUC-19 plasmid ("naked") DNA samples were irradiated by electron-beam or reactor neutron fluxes with doses ranging from 0.9 to 10 kGy. AFM scanning in the tapping mode was used to image and measure the DNA fragment lengths (ranging from a few bp up to 2864 bp long). Double-strand break (DSB) distributions resulting from high-LET neutron and lower-LET electron irradiation revealed a distinct difference between the effects of these two types of radiation: Low-LET radiation-induced DSBs are distributed more uniformly along the DNA, whereas a much larger proportion of neutron-induced DSBs are distributed locally and densely. Furthermore, comparisons with predictions of a random DSB model of radiation damage show that neutron-induced DSBs deviate more from the model than do electron-induced DSBs. In summary, our high-resolution AFM measurements of radiation-induced DNA fragment-length distributions reveal an increased number of very short fragments and hence clustering of DSBs induced by the high-LET neutron radiation compared with low-LET electron radiation and a random DSB model prediction.