Dosimetric Comparisons of Simulation Techniques for Left-Sided Breast Cancer in the COVID-19 Era: Techniques to Reduce Viral Transmission and Respect the Therapeutic Ratio.

Background The COVID-19 pandemic challenges our ability to safely treat breast cancer patients and requires revisiting current techniques to evaluate optimal strategies. Potential long-term sequelae of breast radiation have been addressed by deep inspiration breath-hold (DIBH), prone positioning, and four-dimensional computed tomography (4DCT) average intensity projection (AveIP)-based planning techniques. Dosimetric comparisons to determine the optimal technique to minimize the normal tissue dose for left-sided breast cancers have not been performed. Methods Ten patients with left-sided, early-stage breast cancer undergoing whole breast radiation were simulated in the prone position, supine with DIBH, and with a free-breathing 4DCT scan. The target and organs at risk (OAR) contours were delineated in all scans. Target volume coverage and OAR doses were assessed. One-way analysis of variance (ANOVA) and Kruskal-Wallis one-way ANOVA were used to detect differences in dosimetric parameters among the different treatment plans. Significance was set as p < 0.05. Results We demonstrate differences in heart and lung dose by the simulation technique. The mean heart doses in the prone, DIBH, and AveIP plans were 129 cGy, 154 cGy, and 262 cGy, respectively (p=0.02). The lung V20 in the prone, DIBH, and AveIP groups was 0.5%, 10.3% and 9.5%, respectively (p <0.001). Regardless of technique, lumpectomy planning target volume (PTV) coverage did not differ between the three plans with 95% of the lumpectomy PTV volume covered by 100.4% in prone plans, 98.5% in AveIP plans, and 99.3% in DIBH plans (p=0.7). Conclusions Prone positioning provides dosimetric advantages as compared to DIBH. When infection risks are considered as in the current coronavirus disease 2019 (COVID-19) pandemic, prone plans have advantages in reducing the risk of disease transmission. In instances where prone positioning is not feasible, obtaining an AveIP simulation may be useful in more accurately assessing heart and lung toxicity and informing a risk/benefit discussion of DIBH vs free breath-hold techniques.

Dosimetric Impact of a Tumor Treating Fields Device for Glioblastoma Patients Undergoing Simultaneous Radiation Therapy.

PURPOSE: A recent randomized phase III clinical trial in patients with glioblastoma demonstrated the efficacy of tumor treating fields (TTFields), in which alternating electric fields are applied via transducer arrays to a patient's scalp. This treatment, when added to standard of care therapy, was shown to increase overall survival from 16 to 20.9 months. These results have generated significant interest in incorporating the use of TTFields during postoperative concurrent chemoradiation. However, the dosimetric impact of high-density electrodes on the scalp, within the radiation field, is unknown. METHODS: The dosimetric impact of TTFields electrodes in the radiation field was quantified in two ways: (1) dose calculated in a treatment planning system and (2) physical measurements of surface and deep doses. In the dose calculation comparison, a volumetric-modulated-arc-therapy (VMAT) radiation plan was developed on a CT scan without electrodes and then recalculated with electrodes. For physical measurements, the surface dose underneath TTFields electrodes were measured using a parallel plate ionization chamber and compared to measurements without electrodes for various incident beam angles and for 12 VMAT arc deliveries. Deep dose measurements were conducted for five VMAT plans using Scandidos Delta4 diode array: measured doses on two orthogonal diode arrays were compared. RESULTS: In the treatment planning system, the presence of the TTFields device caused mean reduction of PTV dose of 0.5-1%, and a mean increase in scalp dose of 0.5-1 Gy. Physical measurement showed increases of surface dose directly underneath by 30-110% for open fields with varying beam angles and by 70-160% for VMAT deliveries. Deep dose measurement by diode array showed dose decrease of 1-2% in most areas shadowed by the electrodes (max decrease 2.54%). CONCLUSION: The skin dose in patients being treating with cranial irradiation for glioblastoma may increase substantially (130-260%) with the addition of concurrent TTFields electrodes on the scalp. However, the impact of dose attenuation by the electrodes on deep dose during VMAT treatment is of much smaller, but measureable, magnitude (1-2%). Clinical trials exploring concurrent TTFields with cranial irradiation for glioblastoma may utilize scalp-sparing techniques to mitigate any potential increase in skin toxicity.

Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer.

PURPOSE: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. METHODS AND MATERIALS: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. RESULTS: The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. CONCLUSIONS: It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics.

Active Breathing Coordinator reduces radiation dose to the heart and preserves local control in patients with left breast cancer: report of a prospective trial.

PURPOSE: Incidental radiation dose to the heart and lung during breast radiation therapy (RT) has been associated with an increased risk of cardiopulmonary morbidity. We conducted a prospective trial to determine if RT with the Active Breathing Coordinator (ABC) can reduce the mean heart dose (MHD) by ≥20% and dose to the lung. METHODS AND MATERIALS: Patients with stages 0-III left breast cancer (LBC) were enrolled and underwent simulation with both free breathing (FB) and ABC for comparison of dosimetry. ABC was used during the patient's RT course if the MHD was reduced by ≥5%. The median prescription dose was 50.4 Gy plus a boost in 77 patients (90%). The primary endpoint was the magnitude of MHD reduction when comparing ABC to FB. Secondary endpoints included dose reduction to the heart and lung, procedural success rate, and adverse events. RESULTS: A total of 112 patients with LBC were enrolled from 2002 to 2011 and 86 eligible patients underwent both FB and ABC simulation. Ultimately, 81 patients received RT using ABC, corresponding to 72% procedural success. The primary endpoint was achieved as use of ABC reduced MHD by 20% or greater in 88% of patients (P < .0001). The median values for absolute and relative reduction in MHD were 1.7 Gy and 62%, respectively. RT with ABC provided a statistically significant dose reduction to the left lung. After a median follow up of 81 months, 8-year estimates of locoregional relapse, disease-free, and overall survival were 7%, 90%, and 96%, respectively. CONCLUSIONS: ABC was well tolerated and significantly reduced MHD while preserving local control. Use of the ABC device during RT should be considered to reduce the risk of ischemic heart disease in populations at risk.

High Dose Rate (HDR) Brachytherapy for Mycosis Fungoides of the Wrist.

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma accounting for approximately half of all cutaneous T-cell lymphomas. Radiation therapy is an effective treatment for early stage MF and has been shown to result in long-term disease-free intervals, with even curative potential. Radiation is also effective as palliative treatment for the localized lesion resistant to the topic or other treatments. In the current study, we report using high dose rate (HDR) radiation treatment for a patient with resistant mycosis fungoides involving the wrist. We report a convenient treatment with an ideal radiation dose distribution, and a excellent clinical outcome.

Clinical implementation and failure mode and effects analysis of HDR skin brachytherapy using Valencia and Leipzig surface applicators.

PURPOSE: The planning procedure for Valencia and Leipzig surface applicators (VLSAs) (Nucletron, Veenendaal, The Netherlands) differs substantially from CT-based planning; the unfamiliarity could lead to significant errors. This study applies failure modes and effects analysis (FMEA) to high-dose-rate (HDR) skin brachytherapy using VLSAs to ensure safety and quality. METHOD: A multidisciplinary team created a protocol for HDR VLSA skin treatments and applied FMEA. Failure modes were identified and scored by severity, occurrence, and detectability. The clinical procedure was then revised to address high-scoring process nodes. RESULTS: Several key components were added to the protocol to minimize risk probability numbers. (1) Diagnosis, prescription, applicator selection, and setup are reviewed at weekly quality assurance rounds. Peer review reduces the likelihood of an inappropriate treatment regime. (2) A template for HDR skin treatments was established in the clinic's electronic medical record system to standardize treatment instructions. This reduces the chances of miscommunication between the physician and planner as well as increases the detectability of an error. (3) A screen check was implemented during the second check to increase detectability of an error. (4) To reduce error probability, the treatment plan worksheet was designed to display plan parameters in a format visually similar to the treatment console display, facilitating data entry and verification. (5) VLSAs are color coded and labeled to match the electronic medical record prescriptions, simplifying in-room selection and verification. CONCLUSIONS: Multidisciplinary planning and FMEA increased detectability and reduced error probability during VLSA HDR brachytherapy. This clinical model may be useful to institutions implementing similar procedures.

Iron nitrosyl hemoglobin formation from the reaction of hydroxylamine and hemoglobin under physiological conditions.

Sickle cell disease patients receiving hydroxyurea (HU) therapy have shown increases in the production of nitric oxide (NO) metabolites, which include iron nitrosyl hemoglobin (HbNO), nitrite, and nitrate. However, the exact mechanism by which HU forms HbNO in vivo is not understood. Previous studies indicate that the reaction of oxyhemoglobin (oxyHb) or deoxyhemoglobin (deoxyHb) with HU are too slow to account for in vivo HbNO production. In this study, we show that the reaction of methemoglobin (metHb) with HU to form HbNO could potentially be fast enough to account for in vivo HbNO formation but competing reactions of either excess oxyHb or deoxyHb during the reaction reduces the likelihood that HbNO will be produced from the metHb-HU reaction. Using electron paramagnetic resonance (EPR) spectroscopy we have detected measurable amounts of HbNO and metHb during the reactions of oxyHb, deoxyHb, and metHb with excess hydroxylamine (HA). We also demonstrate HbNO and metHb formation from the reactions of excess oxyHb, deoxyHb, or metHb and HA, conditions that are more likely to mimic those in vivo. These results indicate that the reaction of hydroxylamine with hemoglobin produces HbNO and lend chemical support for a potential role for hydroxylamine in the in vivo metabolism of hydroxyurea.

Urease enhances the formation of iron nitrosyl hemoglobin in the presence of hydroxyurea.

Although it has been shown that hydroxyurea (HU) therapy produces measurable amounts of nitric oxide (NO) metabolites, including iron nitrosyl hemoglobin (HbNO) in patients with sickle cell disease, the in vivo mechanism for formation of these is not known. Much in vitro data and some in vivo data indicates that HU is the NO donor, but other studies suggest a role for nitric oxide synthase (NOS). In this study, we confirm that the NO-forming reactions of HU with hemoglobin (Hb) or other blood constituents is too slow to account for NO production measured in vivo. We hypothesize that, in vivo, HU is partially metabolized to hydroxylamine (HA), which quickly reacts with Hb to form methemoglobin (metHb) and HbNO. We show that addition of urease, which converts HU to HA, to a mixture of blood and HU, greatly enhances HbNO formation.

Effects of iron nitrosylation on sickle cell hemoglobin solubility.

One mechanism by which nitric oxide (NO) has been proposed to benefit patients with sickle cell disease is by reducing intracellular polymerization of sickle hemoglobin (HbS). In this study we have examined the ability of nitric oxide to inhibit polymerization by measuring the solubilizing effect of iron nitrosyl sickle hemoglobin (HbS-NO). Electron paramagnetic resonance spectroscopy was used to confirm that, as found in vivo, the primary type of NO ligation produced in our partially saturated NO samples is pentacoordinate alpha-nitrosyl. Linear dichroism spectroscopy and delay time measurements were used to confirm polymerization. Based on sedimentation studies we found that, although fully ligated (100% tetranitrosyl) HbS is very soluble, the physiologically relevant, partially ligated species do not provide a significant solubilizing effect. The average solubilizing effect of 26% NO saturation was 0.045; much less than the 0.15 calculated for the effect of 26% oxygen saturation. Given the small amounts of NO-ligated hemoglobin achievable through any kind of NO therapy, we conclude that NO therapy does not benefit patients through any direct solubilizing effect.