Comparison of Three Groups of Patients Having Low Dose Rate Prostate Brachytherapy: Prostate-Specific Antigen Failure and Overall Survival.

Purpose To examine dosimetric and clinical outcomes for Cs-131 radioactive seed implant compared to Pd-103 and I-125.  Background/Significance Cs-131 is a novel isotope with relatively short half-life (9.7 days) that may have clinical advantages in seed implant treatments of prostate cancers. There may be a shorter duration of symptoms and increased PSA control rates. Methods We performed a retrospective study in which clinical and dosimetric outcomes were compared for 186 prostate implants performed over a ten-year time period at three different Ascension hospitals. Isotopes that were used included Cs-131 (n=66; half-life 9.7 days), I-125 (n=60; half-life 60 days), and Pd-103 (n=60; half-life 17 days) Results The implants used standard radiation dosages. These were 145 Gy for I-125 alone or 109 Gy when combined with external beam radiation. In the case of Cs-131 used alone, the dose was 115 Gy or 85 Gy when combined with an external beam. For Pd-103, 125 Gy was used for monotherapy and 90 Gy when combined with an external beam. The Cs-131 dosimetry was found to be similar to I-125 and Pd-103 on a quantitative basis. However, there was better homogeneity, and the delivered activity per seed and the number of seeds employed were greater compared to other isotopes. We compared the corrected total source strengths (i.e. normalized to sample mean values) and were able to demonstrate similar distributions for the three isotopes. Dosimetric analysis also suggested there was superior homogeneity with Cs-131. The median PSA value at 60 months was 0.11 ng/ml. There were only a few PSA failures in the three groups of cases, nonetheless, the Cs-131 had the fewest.  Conclusions One attractive option for men with early-stage prostate cancer is interstitial brachytherapy. The use of the shorter-acting Cs-131 isotope may be expected to have dose-related side effects that resolve more rapidly. This series suggests a trend for improved PSA control outcomes for Cs-131 patients compared with I-125 and Pd-103.

Validation of RTOG 0813 Proximal Bronchial Tree Constraints for Pulmonary Toxicity With Stereotactic Body Radiation Therapy for Central Non-small Cell Lung Cancer.

PURPOSE: Clinical validation of protocol-specified dosimetric constraints for the proximal bronchial tree (PBT) is limited for central non-small cell lung cancer treated with stereotactic body radiation therapy. We sought to validate Radiation Therapy Oncology Group (RTOG) PBT constraints with a large institutional data set. METHODS AND MATERIALS: Lesions ≤2 cm from the PBT treated with definitive stereotactic body radiation therapy from 2009 to 2016 were identified from a prospective registry of 1462 patients. Every PBT dose and volume combination, ranging from 0 cGy to 8000 cGy in increments of 10 cGy and volumes ranging from 0.03 cm3 to 50 cm3 in increments of 0.03 cm3, was analyzed. The sensitivity and specificity of these endpoints for identifying pulmonary toxicity were calculated. Pulmonary toxicity was classified as pneumonitis or nonpneumonitis toxicity (NPT) (fistula, stenosis, necrosis, hemoptysis, clinically significant pleural effusion). The optimal dosimetric predictor was chosen by calculation of F-score (highest sensitivity and specificity). RESULTS: The study included 132 patients, with 26.0-month median follow-up. Eight grade ≥2 NPT (2 grade 5) and 8 grade 2 pneumonitis toxicities were observed. The PBT dosimetric endpoint with the highest F-score for identification of grade 2 to 5 NPT was D0.03cc ≤5000 cGy and that for grade 3 to 5 NPT was D0.33cc ≤4710 cGy, with sensitivity and specificity of 87.5% and 76.6% and 100.0% and 85.7%, respectively. Applying the RTOG 0813 PBT constraints to our data set achieved a sensitivity and specificity of 33.3% and 92.1% for D4cc ≤1800 cGy and 37.5% and 92.7% for D0.03cc ≤5250 cGy for identification of grade 2 to 5 NPT. A PBT dosimetric correlation for pneumonitis toxicity could not be identified. CONCLUSIONS: This novel dosimetric analysis validates current RTOG constraints and emphasizes high-dose, small-volume constraints as better predictors for NPT. We demonstrated that a slightly lower maximum point dose PBT constraint may be optimal for identification of NPT. Validation of these findings in a larger cohort of patients with longer follow-up is necessary.

Investigation of brachial plexus dose that exceeds RTOG constraints for apical lung tumors treated with four- or five-fraction stereotactic body radiation therapy.

PURPOSE/OBJECTIVESS: We sought to determine the rate of brachial plexopathy (BPX) in patients exceeding RTOG dose constraints for treatment of apical lung tumors. MATERIALS/METHODS: Patients with apical lung tumors treated with four- or five-fraction SBRT were identified from a prospective registry. Dosimetric data were obtained for ipsilateral subclavian vein (SCV) and anatomic BP (ABP) contours. Cumulative equivalent dose in 2 Gy equivalents (EQD2) was calculated for the SCV contour in patients with a history of prior ipsilateral RT. Five-fraction SBRT RTOG constraints of D0.03cc ≤32.0 Gy and D3cc ≤30.0 Gy were used. BPX was graded according to Common Terminology Criteria for Adverse Events 3.0. RESULTS: A total of 64 patients met inclusion criteria. Median follow-up was 21 months. Six patients (9.4%) had prior ipsilateral conventional fractionated RT with varying degrees of overlap with subsequent SBRT field. Eleven patients without prior ipsilateral RT exceeded D0.03cc ≤32.0 Gy to SCV (mean 43.8 Gy ± 5.8). No BPX was observed in these patients. Out of the six patients who had prior ipsilateral RT, three patients exceeded D0.03cc ≤32.0 Gy to SCV (44.2 Gy ± 11.3), with two of these patients developing Grade 2 BPX within one year of SBRT. The EQD2 cumulative maximum point dose to BP was 122.6 Gy and 184.7 Gy for the two patients who developed Grade 2 BPX. The D0.03cc was >10 Gy higher to the ABP contour than the SCV contour in 14 patients. CONCLUSION: Without a history of prior ipsilateral RT, no BPX was observed at 21 month follow-up in 11 patients who exceeded the RTOG five-fraction BP constraint. This observation is hypothesis generating and more experience with longer follow-up is necessary to validate these findings. For tumors located in close proximity to apical structures, there was substantial variation in dose between the ABP and SCV contours.

Effect of Tumor Location and Dosimetric Predictors for Chest Wall Toxicity in Single-Fraction Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.

PURPOSE: Dosimetric parameters to limit chest wall toxicity (CWT) are not well defined in single-fraction (SF) stereotactic body radiation therapy (SBRT) phase 2 trials. We sought to determine the relationship of tumor location and dosimetric parameters with CWT for SF-SBRT. METHODS AND MATERIALS: From a prospective registry of 1462 patients, we identified patients treated with 30 Gy or 34 Gy. Gross tumor volume was measured as abutting, ≤1 cm, 1 to 2 cm, or >2 cm from the chest wall. CWT was prospectively graded according to Common Terminology Criteria for Adverse Events version 3.0, with grade 2 requiring medical therapy, grade 3 requiring procedural intervention, and grade 4 being disabling pain. Grade 1 CWT or radiographic rib fracture was not included. Logistic regression analysis was used to identify the parameters associated with CWT and calculate the probability of CWT with dose. RESULTS: This study included 146 lesions. The median follow-up time was 23.8 months. The 5-year local control, distant metastasis, and overall survival rates were 91.8%, 19.2%, and 28.7%, respectively. Grade 2 to 4 CWT was 30.6% for lesions abutting the chest wall, 8.2% for ≤1 cm from the chest wall, 3.8% for 1 to 2 cm from the chest wall, and 5.7% for >2 cm from the chest wall. Grade ≥3 CWT was 1.4%. Tumor abutment (odds ratio [OR]: 6.5; P = .0005), body mass index (OR: 1.1; P = .02), rib D1cc (OR: 1.01/Gy; P = .03), chest wall D1cc (OR: 1.08/Gy; P = .03), and chest wall D5cc (OR: 1.10/Gy; P = .01) were significant predictors for CWT on univariate analysis. Tumor abutment was significant for CWT (OR: 7.5; P = .007) on multivariate analysis. The probability of CWT was 15% with chest wall D5cc at 27.2 Gy and rib D1cc at 30.2 Gy. CONCLUSIONS: The rate of CWT with SF-SBRT is similar to the rates published for fractionated SBRT, with most CWT being low grade. Tumor location relative to the chest wall is not a contraindication to SF-SBRT, but the rates increase significantly with abutment. Rib D1cc and chest wall D1cc and D5cc may be used as predictors of CWT.

Abscopal Effect after Radiosurgery for Solitary Brain Metastasis from Non-small Cell Lung Cancer.

The abscopal effect is a phenomenon relating to the treatment of metastatic cancer in which localized irradiation to a tumor concurrently causes shrinkage of tumors distant from the area of treatment. Localized radiotherapy is thought to cause anti-tumor immunologic responses that lead to regression and remission of cancers distant to the initial location of treatment. We present a 47-year-old male with brain metastasis from non-small cell lung cancer (NSCLC) who went into remission following stereotactic radiosurgery treatment to a brain lesion, in the absence of systemic treatment. We discuss the novelty of this case and its importance to future research on the abscopal effect. Though it is difficult to distinguish the abscopal effect from spontaneous remission of non-targeted cancer, this report sheds insight on the potential for improving treatment for the leading cause of cancer death worldwide.

Assessment of a multi-layered diffuse correlation spectroscopy method for monitoring cerebral blood flow in adults.

Diffuse correlation spectroscopy (DCS) is a promising technique for brain monitoring as it can provide a continuous signal that is directly related to cerebral blood flow (CBF); however, signal contamination from extracerebral tissue can cause flow underestimations. The goal of this study was to investigate whether a multi-layered (ML) model that accounts for light propagation through the different tissue layers could successfully separate scalp and brain flow when applied to DCS data acquired at multiple source-detector distances. The method was first validated with phantom experiments. Next, experiments were conducted in a pig model of the adult head with a mean extracerebral tissue thickness of 9.8 ± 0.4 mm. Reductions in CBF were measured by ML DCS and computed tomography perfusion for validation; excellent agreement was observed by a mean difference of 1.2 ± 4.6% (CI95%: -31.1 and 28.6) between the two modalities, which was not significantly different.

Assessment of the best flow model to characterize diffuse correlation spectroscopy data acquired directly on the brain.

Diffuse correlation spectroscopy (DCS) is a non-invasive optical technique capable of monitoring tissue perfusion. The normalized temporal intensity autocorrelation function generated by DCS is typically characterized by assuming that the movement of erythrocytes can be modeled as a Brownian diffusion-like process instead of by the expected random flow model. Recently, a hybrid model, referred to as the hydrodynamic diffusion model, was proposed, which combines the random and Brownian flow models. The purpose of this study was to investigate the best model to describe autocorrelation functions acquired directly on the brain in order to avoid confounding effects of extracerebral tissues. Data were acquired from 11 pigs during normocapnia and hypocapnia, and flow changes were verified by computed tomography perfusion (CTP). The hydrodynamic diffusion model was found to provide the best fit to the autocorrelation functions; however, no significant difference for relative flow changes measured by the Brownian and hydrodynamic diffusion models was observed.

The influence of Trp53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells.

Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/-) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.

Quantifying the cerebral metabolic rate of oxygen by combining diffuse correlation spectroscopy and time-resolved near-infrared spectroscopy.

Preterm infants are highly susceptible to ischemic brain injury; consequently, continuous bedside monitoring to detect ischemia before irreversible damage occurs would improve patient outcome. In addition to monitoring cerebral blood flow (CBF), assessing the cerebral metabolic rate of oxygen (CMRO2) would be beneficial considering that metabolic thresholds can be used to evaluate tissue viability. The purpose of this study was to demonstrate that changes in absolute CMRO2 could be measured by combining diffuse correlation spectroscopy (DCS) with time-resolved near-infrared spectroscopy (TR-NIRS). Absolute CBF was determined using bolus-tracking TR-NIRS to calibrate the DCS measurements. Cerebral venous blood oxygenation (SvO2) was determined by multiwavelength TR-NIRS measurements, the accuracy of which was assessed by directly measuring the oxygenation of sagittal sinus blood. In eight newborn piglets, CMRO2 was manipulated by varying the anesthetics and by injecting sodium cyanide. No significant differences were found between the two sets of SvO2 measurements obtained by TR-NIRS or sagittal sinus blood samples and the corresponding CMRO2 measurements. Bland-Altman analysis showed a mean CMRO2 difference of 0.0268 ± 0.8340 mLO2/100 g/min between the two techniques over a range from 0.3 to 4 mL O2/100 g/min.

Calibration of diffuse correlation spectroscopy with a time-resolved near-infrared technique to yield absolute cerebral blood flow measurements.

A primary focus of neurointensive care is the prevention of secondary brain injury, mainly caused by ischemia. A noninvasive bedside technique for continuous monitoring of cerebral blood flow (CBF) could improve patient management by detecting ischemia before brain injury occurs. A promising technique for this purpose is diffuse correlation spectroscopy (DCS) since it can continuously monitor relative perfusion changes in deep tissue. In this study, DCS was combined with a time-resolved near-infrared technique (TR-NIR) that can directly measure CBF using indocyanine green as a flow tracer. With this combination, the TR-NIR technique can be used to convert DCS data into absolute CBF measurements. The agreement between the two techniques was assessed by concurrent measurements of CBF changes in piglets. A strong correlation between CBF changes measured by TR-NIR and changes in the scaled diffusion coefficient measured by DCS was observed (R(2) = 0.93) with a slope of 1.05 ± 0.06 and an intercept of 6.4 ± 4.3% (mean ± standard error).

210Pb concentration in household dust: a potential indicator of long-term indoor radon exposure.

Radon decays to a long-lived isotope 210Pb with a half-life of about 22 years. Measuring concentrations of 210Pb in household dust could be an alternative method of determining indoor radon levels. This novel method for estimating long-term radon concentration was explored in over a hundred Canadian residential homes. The results demonstrate that 210Pb concentrations in household dust relate reasonably well to radon concentrations in homes.

An estimation of Canadian population exposure to cosmic rays.

The worldwide average exposure to cosmic rays contributes to about 16% of the annual effective dose from natural radiation sources. At ground level, doses from cosmic ray exposure depend strongly on altitude, and weakly on geographical location and solar activity. With the analytical model PARMA developed by the Japan Atomic Energy Agency, annual effective doses due to cosmic ray exposure at ground level were calculated for more than 1,500 communities across Canada which cover more than 85% of the Canadian population. The annual effective doses from cosmic ray exposure in the year 2000 during solar maximum ranged from 0.27 to 0.72 mSv with the population-weighted national average of 0.30 mSv. For the year 2006 during solar minimum, the doses varied between 0.30 and 0.84 mSv, and the population-weighted national average was 0.33 mSv. Averaged over solar activity, the Canadian population-weighted average annual effective dose due to cosmic ray exposure at ground level is estimated to be 0.31 mSv.