Obtaining organ-specific radiobiological parameters from clinical data for radiation therapy planning of head and neck cancers.

Objective.Different radiation therapy (RT) strategies, e.g. conventional fractionation RT (CFRT), hypofractionation RT (HFRT), stereotactic body RT (SBRT), adaptive RT, and re-irradiation are often used to treat head and neck (HN) cancers. Combining and/or comparing these strategies requires calculating biological effective dose (BED). The purpose of this study is to develop a practical process to estimate organ-specific radiobiologic model parameters that may be used for BED calculations in individualized RT planning for HN cancers.Approach.Clinical dose constraint data for CFRT, HFRT and SBRT for 5 organs at risk (OARs) namely spinal cord, brainstem, brachial plexus, optic pathway, and esophagus obtained from literature were analyzed. These clinical data correspond to a particular endpoint. The linear-quadratic (LQ) and linear-quadratic-linear (LQ-L) models were used to fit these clinical data and extract relevant model parameters (alpha/beta ratio, gamma/alpha,dTand BED) from the iso-effective curve. The dose constraints in terms of equivalent physical dose in 2 Gy-fraction (EQD2) were calculated using the obtained parameters.Main results.The LQ-L and LQ models fitted clinical data well from the CFRT to SBRT with the LQ-L representing a better fit for most of the OARs. The alpha/beta values for LQ-L (LQ) were found to be 2.72 (2.11) Gy, 0.55 (0.30) Gy, 2.82 (2.90) Gy, 6.57 (3.86) Gy, 5.38 (4.71) Gy, and the dose constraint EQD2 were 55.91 (54.90) Gy, 57.35 (56.79) Gy, 57.54 (56.35) Gy, 60.13 (59.72) Gy and 65.66 (64.50) Gy for spinal cord, optic pathway, brainstem, brachial plexus, and esophagus, respectively. Additional two LQ-L parametersdTwere 5.24 Gy, 5.09 Gy, 7.00 Gy, 5.23 Gy, and 6.16 Gy, and gamma/alpha were 7.91, 34.02, 8.67, 5.62 and 4.95.Significance.A practical process was developed to extract organ-specific radiobiological model parameters from clinical data. The obtained parameters can be used for biologically based radiation planning such as calculating dose constraints of different fractionation regimens.

A general framework to develop a radiomic fingerprint for progression-free survival in cervical cancer.

PURPOSE: Treatment of locally advanced cervical cancer patients includes chemoradiation followed by brachytherapy. Our aim is to develop a delta radiomics (DRF) model from MRI-based brachytherapy treatment and assess its association with progression free survival (PFS). MATERIALS AND METHODS: A retrospective analysis of FIGO stage IB- IV cervical cancer patients between 2012 and 2018 who were treated with definitive chemoradiation followed by MRI-based intracavitary brachytherapy was performed. Clinical factors together with 18 radiomic features extracted from different radiomics matrices were analyzed. The delta radiomic features (DRFs) were extracted from MRI on the first and last brachytherapy fractions. Support Vector Machine (SVM) models were fitted to combinations of 2-3 DRFs found significant after Spearman correlation and Wilcoxon rank sum test statistics. Additional models were tested that included clinical factors together with DRFs. RESULTS: A total of 39 patients were included in the analysis with a median patient age of 52 years. Progression occurred in 20% of patients (8/39). The significant DRFs using two DRF feature combinations was a model using auto correlation (AC) and sum variance (SV). The best performing three feature model combined mean, AC & SV. Additionally, the inclusion of FIGO stages with the 2- and 3 DRF combination model(s) improved performance compared to models with only DRFs. However, all the clinical factor + DRF models were not significantly different from one another (all AUCs were 0.77). CONCLUSIONS: Our study shows promising evidence that radiomics metrics are associated with progression free survival in cervical cancer.

Tumor Control Probability Modeling for Radiation Therapy of Keratinocyte Carcinoma.

SUMMARY: Skin cancer patients may be treated definitively using radiation therapy (RT) with electrons, kilovoltage, or megavoltage photons depending on tumor stage and invasiveness. This study modeled tumor control probability (TCP) based on the pooled clinical outcome data of RT for primary basal and cutaneous squamous cell carcinomas (BCC and cSCC, respectively). Four TCP models were developed and found to be potentially useful in developing optimal treatment schemes based on recommended ASTRO 2020 Skin Consensus Guidelines for primary, keratinocyte carcinomas (i.e. BCC and cSCC). BACKGROUND: Radiotherapy (RT) with electrons or photon beams is an excellent primary treatment option for keratinocyte carcinoma (KC), particularly for non-surgical candidates. Our objective is to model tumor control probability (TCP) based on the pooled clinical data of primary basal and cutaneous squamous cell carcinomas (BCC and cSCC, respectively) in order to optimize treatment schemes. METHODS: Published reports citing crude estimates of tumor control for primary KCs of the head by tumor size (diameter: ≤2 cm and >2 cm) were considered in our study. A TCP model based on a sigmoidal function of biological effective dose (BED) was proposed. Three-parameter TCP models were generated for BCCs ≤2 cm, BCCs >2cm, cSCCs ≤2 cm, and cSCCs >2 cm. Equivalent fractionation schemes were estimated based on the TCP model and appropriate parameters. RESULTS: TCP model parameters for both BCC and cSCC for tumor sizes ≤2 cm and >2cm were obtained. For BCC, the model parameters were found to be TD50 = 56.62 ± 6.18 × 10-3 Gy, k = 0.14 ± 2.31 × 10-2 Gy-1 and L = 0.97 ± 4.99 × 10-3 and TD50 = 55.78 ± 0.19 Gy, k = 1.53 ± 0.20 Gy-1 and L = 0.94 ± 3.72 × 10-3 for tumor sizes of ≤2 cm and >2 cm, respectively. For SCC the model parameters were found to be TD50 = 56.81 ± 19.40 × 104 Gy, k = 0.13 ± 7.92 × 104 Gy-1 and L = 0.96 ± 1.31 × 10-2 and TD50 = 58.44 ± 0.30 Gy, k = 2.30 ± 0.43 Gy-1 and L = 0.91± 1.22 × 10-2 for tumors ≤2cm and >2 cm, respectively. The TCP model with the derived parameters predicts that radiation regimens with higher doses, such as increasing the number of fractions and/or dose per fraction, lead to higher TCP, especially for KCs >2 cm in size. CONCLUSION: Four TCP models for primary KCs were developed based on pooled clinical data that may be used to further test the recommended kV and MV x-ray and electron RT regimens from the 2020 ASTRO guidelines. Increasing both number of fractions and dose per fraction may have clinically significant effects on tumor control for tumors >2 cm in size for both BCC and cSCC.

Maximizing Tumor Control and Limiting Complications With Stereotactic Body Radiation Therapy for Pancreatic Cancer.

PURPOSE: Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiation therapy is being increasingly used for pancreatic cancer (PCa), particularly in patients with locally advanced and borderline resectable disease. A wide variety of dose fractionation schemes have been reported in the literature. This HyTEC review uses tumor control probability models to evaluate the comparative effectiveness of the various SBRT treatment regimens used in the treatment of patients with localized PCa. METHODS AND MATERIALS: A PubMed search was performed to review the published literature on the use of hypofractionated SBRT (usually in 1-5 fractions) for PCa in various clinical scenarios (eg, preoperative [neoadjuvant], borderline resectable, and locally advanced PCa). The linear quadratic model with α/ß= 10 Gy was used to address differences in fractionation. Logistic tumor control probability models were generated using maximum likelihood parameter fitting. RESULTS: After converting to 3-fraction equivalent doses, the pooled reported data and associated models suggests that 1-year local control (LC) without surgery is ≈79% to 86% after the equivalent of 30 to 36 Gy in 3 fractions, showing a dose response in the range of 25 to 36 Gy, and decreasing to less than 70% 1-year LC at doses below 24 Gy in 3 fractions. The 33 Gy in 5 fraction regimen (Alliance A021501) corresponds to 28.2 Gy in 3 fractions, for which the HyTEC pooled model had 77% 1-year LC without surgery. Above an equivalent dose of 28 Gy in 3 fractions, with margin-negative resection the 1-year LC exceeded 90%. CONCLUSIONS: Pooled analyses of reported tumor control probabilities for commonly used SBRT dose-fractionation schedules for PCa suggests a dose response. These findings should be viewed with caution given the challenges and limitations of this review. Additional data are needed to better understand the dose or fractionation-response of SBRT for PCa.

A Pilot Study of Cardiac MRI in Breast Cancer Survivors After Cardiotoxic Chemotherapy and Three-Dimensional Conformal Radiotherapy.

PURPOSE/OBJECTIVES: Node-positive breast cancer patients often receive chemotherapy and regional nodal irradiation. The cardiotoxic effects of these treatments, however, may offset some of the survival benefit. Cardiac magnetic resonance (CMR) is an emerging modality to assess cardiac injury. This is a pilot trial assessing cardiac damage using CMR in patients who received anthracycline-based chemotherapy and three-dimensional conformal radiotherapy (3DCRT) regional nodal irradiation using heart constraints. MATERIALS AND METHODS: Node-positive breast cancer patients (2000-2008) treated with anthracycline-based chemotherapy and 3DCRT regional nodal irradiation (including the internal mammary chain nodes) with heart ventricular constraints (V25 < 10%) were invited to participate. Cardiac tissues were contoured and analyzed separately for whole heart (pericardium) and for combined ventricles and left atrium (myocardium). CMR obtained ventricular function/dimensions, late gadolinium enhancement (LGE), global longitudinal strain (GLS), and extracellular volume fraction (ECV) as measures of cardiac injury and/or early fibrosis. CMR parameters were correlated with dose-volume constraints using Spearman correlations. RESULTS: Fifteen left-sided and five right-sided patients underwent CMR. Median diagnosis age was 50 (32-77). No patients had baseline cardiac disease before regional nodal irradiation. Median time after 3DCRT was 8.3 years (5.2-14.4). Median left-sided mean heart dose (MHD) was 4.8 Gy (1.1-11.2) and V25 was 5.7% (0-12%). Median left ventricular ejection fraction (LVEF) was 63%. No abnormal LGE was observed. No correlations were seen between whole heart doses and LVEF, LV mass, GLS, or LV dimensions. Increasing ECV did not correlate with increased heart or ventricular doses. However, correlations between higher LV mass and ventricular mean dose, V10, and V25 were seen. CONCLUSION: At a median follow-up of 8.3 years, this cohort of node-positive breast cancer patients who received anthracycline-based chemotherapy and regional nodal irradiation had no clinically abnormal CMR findings. However, correlations between ventricular mean dose, V10, and V25 and LV mass were seen. Larger corroborating studies that include advanced techniques for measuring regional heart mechanics are warranted.

Development of an imaging modality utilizing 2D optical signals during an EPI-fluorescent optical mapping experiment.

Optical mapping is a commonly used technique to visualize the electrical activity in the heart. Recently, several groups have attempted to use the signals acquired in optical mapping to image the transmembrane potential in the heart, which would be particularly advantageous when studying the effects of defibrillation-type shocks throughout the wall of the heart. Our work presents an alternative imaging method that makes use of data obtained using multiple wavelengths and therefore multiple optical decay constants. A modified form of the diffusion equation Green's function for a semi-infinite slab of tissue is derived and used to relate the detected optical signals to the source of emission photons. Images using the optical signals are reconstructed using Gaussian quadrature and matrix inversion. Our results show that images can be obtained for source terms located below the tissue surface. Furthermore, we demonstrate that our reconstruction method's susceptibility to noise can be alleviated using sophisticated matrix inverse techniques, such as singular value decomposition. Sources that rapidly decay with depth or are highly localized in the image plane require more sophisticated techniques (e.g., regularization methods) to image the electrical activity in the heart. The work presented here demonstrates the feasibility of a new imaging technique of cardiac electrical activity using optical mapping.

Calculation of optical signal using three-dimensional bidomain/diffusion model reveals distortion of the transmembrane potential.

Optical mapping experiments allow investigators to view the effects of electrical currents on the transmembrane potential, V(m), as a shock is applied to the heart. One important consideration is whether the optical signal accurately represents V(m). We have combined the bidomain equations along with the photon diffusion equation to study the excitation and emission of photons during optical mapping of cardiac tissue. Our results show that this bidomain/diffusion model predicts an optical signal that is much smaller than V(m) near a stimulating electrode, a result consistent with experimental observations. Yet, this model, which incorporates the effect of lateral averaging, also reveals an optical signal that overestimates V(m) at distances >1 mm away from the electrode. Although V(m) falls off with distance r from the electrode as exp(-r/lambda)/r, the optical signal decays as a simple exponential, exp(-r/lambda). Moreover, regions of hyperpolarization adjacent to a cathode are emphasized in the optical signal compared to the region of depolarization under the cathode. Imaging methods utilizing optical mapping techniques will need to account for these distortions to accurately reconstruct V(m).

Electrostriction of anisotropic tissue.

The electrostrictive effects in anisotropic tissue, such as muscle, are interesting and qualitatively different than in an isotropic material. A striking feature in anisotropic tissue is the presence of a charge distribution, which is absent in isotropic tissue. This charge interacts with the electric field to give rise to body forces that deform the tissue. We develop an electromechanical model to investigate how anisotropic tissue deforms due to an electric field, and find analytical solutions for the pressure and displacement. The distribution of the pressure and displacement are complex and dependent on the boundary conditions. The effects of electrostriction are small, but comparable in size to pressures and displacements in other imaging modalities that utilize similar mechanical effects.

Association of Locoregional Control With High Body Mass Index in Women Undergoing Breast Conservation Therapy for Early-Stage Breast Cancer.

PURPOSE: Obesity, as measured by the body mass index (BMI), is a risk factor for distant recurrence and decreased survival in breast cancer. We sought to determine whether the BMI correlated with local recurrence and reduced survival in a cohort of predominantly obese women treated with breast conservation therapy. METHODS AND MATERIALS: From 1998 to 2010, 154 women with early-stage invasive breast cancer and 39 patients with ductal carcinoma in situ underwent prone whole breast irradiation. Cox proportional hazards regression, Kaplan-Meier methods with the log-rank test, and multivariate analysis were used to explore the association of the outcomes with the BMI. RESULTS: The median patient age was 60 years, and the median follow-up duration was 73 months. The median BMI was 33.2 kg/m(2); 91% of the patients were overweight (BMI ≥25 kg/m(2)) and 69% of the patients were clinically obese (BMI ≥30 kg/m(2)). The BMI was significantly associated with the locoregional recurrence-free interval for patients with invasive cancer and ductal carcinoma in situ (hazard ratio [HR], 1.09; P=.047). Also, a trend was seen for increased locoregional recurrence with a higher BMI (P=.09) for patients with invasive disease, which was significant when examining the outcomes with a BMI stratified by the median value of 33.2 kg/m(2) (P=.008). A greater BMI was also significantly associated with decreased distant recurrence-free interval (HR, 1.09; P=.011) and overall survival (HR, 1.09; P=.004); this association remained on multivariate analysis (distant recurrence-free interval, P=.034; overall survival, P=.0007). CONCLUSIONS: These data suggest that the BMI might affect the rate of locoregional recurrence in breast cancer patients. A higher BMI predicted a worse distant recurrence-free interval and overall survival. The present investigation adds to the increasing evidence that BMI is an important prognostic factor in early-stage breast cancer treated with breast conservation therapy.

Consolidating duodenal and small bowel toxicity data via isoeffective dose calculations based on compiled clinical data.

PURPOSE: To consolidate duodenum and small bowel toxicity data from clinical studies with different dose fractionation schedules using the modified linear quadratic (MLQ) model. A methodology of adjusting the dose-volume (D,v) parameters to different levels of normal tissue complication probability (NTCP) was presented. METHODS AND MATERIALS: A set of NTCP model parameters for duodenum toxicity were estimated by the χ(2) fitting method using literature-based tolerance dose and generalized equivalent uniform dose (gEUD) data. These model parameters were then used to convert (D,v) data into the isoeffective dose in 2 Gy per fraction, (D(MLQED2),v) and convert these parameters to an isoeffective dose at another NTCP (D(MLQED2'),v). RESULTS: The literature search yielded 5 reports useful in making estimates of duodenum and small bowel toxicity. The NTCP model parameters were found to be TD50(1)(model) = 60.9 ± 7.9 Gy, m = 0.21 ± 0.05, and δ = 0.09 ± 0.03 Gy(-1). Isoeffective dose calculations and toxicity rates associated with hypofractionated radiation therapy reports were found to be consistent with clinical data having different fractionation schedules. Values of (D(MLQED2'),v) between different NTCP levels remain consistent over a range of 5%-20%. CONCLUSIONS: MLQ-based isoeffective calculations of dose-response data corresponding to grade ≥2 duodenum toxicity were found to be consistent with one another within the calculation uncertainty. The (D(MLQED2),v) data could be used to determine duodenum and small bowel dose-volume constraints for new dose escalation strategies.

A phase I/II study piloting accelerated partial breast irradiation using CT-guided intensity modulated radiation therapy in the prone position.

BACKGROUND AND PURPOSE: External beam accelerated partial breast irradiation (EB-aPBI) is noninvasive with broader potential applicability than aPBI using brachytherapy. However, it has inherent challenges in daily reproducibility. Image-guide radiotherapy (IGRT) can improve daily reproducibility, allowing smaller treatment margins. Our institution proposed IG-IMRT in the prone position to evaluate dose homogeneity, conformality, normal tissue avoidance, and reliable targeting for EB-aPBI. We report preliminary results and toxicity from a phase I/II study evaluating the feasibility of EB-aPBI in the prone position using IG-IMRT. MATERIALS AND METHODS: Twenty post-menopausal women with node-negative breast cancer, excised tumors <3.0 cm, negative sentinel lymph node biopsy, and surgical clips demarcating the lumpectomy cavity underwent prone EB-aPBI using IG-IMRT on an IRB-approved phase I/II study. All patients underwent CT planning in the prone position. The lumpectomy cavity PTV represented a 2.0 cm expansion. 38.5 Gy was delivered in 10 fractions over 5 days, such that 95% of the prescribed dose covered >99% of the PTV. Dose constraints for the whole breast, lungs and heart were met. RESULTS: The median patient age was 61.5. Mean tumor size was 1.0 cm. 35% of patients had DCIS. Median PTV was 243 cc (108-530) and median breast reference volume was 1698 cc (647-3627). Average daily shifts for IGRT were (0.6, -4.6, 1.7 mm) with standard deviations of (6.3, 6.5, 6.4mm). Acute toxicity was G1 erythema in 80%, and G2 erythema, G2 fatigue, and G2 breast pain each occurred in 1 patient. With a median follow-up of 18.9 months (12-35), 40% of patients have G1 fibrosis and 30% have G1 hyperpigmentation. 95% of patients have good to excellent cosmesis. There have been no recurrences. CONCLUSIONS: These data demonstrate that EB-aPBI in the prone position using IG-IMRT is well tolerated, yields good dosimetric conformality, and results in promising early toxicity profiles.

Consolidating risk estimates for radiation-induced complications in individual patient: late rectal toxicity.

PURPOSE: To test the feasibility of a new approach to synthesize published normal tissue complication data using late rectal toxicity in prostate cancer as an example. METHODS AND MATERIALS: A data survey was performed to identify the published reports on the dose-response relationships for late rectal toxicity. The risk estimates for Grade 1 or greater, Grade 2 or greater, and Grade 3 or greater toxicity were obtained for a test cohort of patients treated at our institution. The influence of the potential factors that might have affected the reported toxicity levels was investigated. The studies that did not conform to the general data trends were excluded, and single, combined risk estimates were derived for each patient and toxicity level. RESULTS: A total of 21 studies of nonoverlapping patient populations were identified. Three studies provided dose-response models for more than one level of toxicity. Of these 21 studies, 6, 14, and 5 were used to derive the initial risk estimates for Grade 1, 2, and 3 or greater toxicity, respectively. A comparison of risk estimates between the studies reporting rectal bleeding and rectal toxicity (bleeding plus other symptoms) or between studies with follow-up <36 months and ≥36 months did not reveal significant differences (p ≥ .29 for all comparisons). After excluding three reports that did not conform to the general data trends, the combined risk estimates were derived from 5 reports (647 patients), 11 reports (3,369 patients), and 5 reports (1,330 patients) for Grade 1, 2, and 3 or greater toxicity, respectively. CONCLUSIONS: The proposed approach is feasible and allows for more systematic use of published dose-response data to estimate the complication risks for the individual patient.