CT-derived radiomic features to discriminate histologic characteristics of pancreatic neuroendocrine tumors.

PURPOSE: To assess the ability of radiomic features (RF) extracted from contrast-enhanced CT images (ceCT) and non-contrast-enhanced (non-ceCT) in discriminating histopathologic characteristics of pancreatic neuroendocrine tumors (panNET). METHODS: panNET contours were delineated on pre-surgical ceCT and non-ceCT. First- second- and higher-order RF (adjusted to eliminate redundancy) were extracted and correlated with histological panNET grade (G1 vs G2/G3), metastasis, lymph node invasion, microscopic vascular infiltration. Mann-Whitney with Bonferroni corrected p values assessed differences. Discriminative power of significant RF was calculated for each of the end-points. The performance of conventional-imaged-based-parameters was also compared to RF. RESULTS: Thirty-nine patients were included (mean age 55-years-old; 24 male). Mean diameters of the lesions were 24 × 27 mm. Sixty-nine RF were considered. Sphericity could discriminate high grade tumors (AUC = 0.79, p = 0.002). Tumor volume (AUC = 0.79, p = 0.003) and several non-ceCT and ceCT RF were able to identify microscopic vascular infiltration: voxel-alignment, neighborhood intensity-difference and intensity-size-zone families (AUC ≥ 0.75, p < 0.001); voxel-alignment, intensity-size-zone and co-occurrence families (AUC ≥ 0.78, p ≤ 0.002), respectively). Non-ceCT neighborhood-intensity-difference (AUC = 0.75, p = 0.009) and ceCT intensity-size-zone (AUC = 0.73, p = 0.014) identified lymph nodal invasion; several non-ceCT and ceCT voxel-alignment family features were discriminative for metastasis (p < 0.01, AUC = 0.80-0.85). Conventional CT 'necrosis' could discriminate for microscopic vascular invasion (AUC = 0.76, p = 0.004) and 'arterial vascular invasion' for microscopic metastasis (AUC = 0.86, p = 0.001). No conventional-imaged-based-parameter was significantly associated with grade and lymph node invasion. CONCLUSIONS: Radiomic features can discriminate histopathology of panNET, suggesting a role of radiomics as a non-invasive tool for tumor characterization. TRIAL REGISTRATION NUMBER: NCT03967951, 30/05/2019.

Acute patient-reported intestinal toxicity in whole pelvis IMRT for prostate cancer: Bowel dose-volume effect quantification in a multicentric cohort study.

BACKGROUND AND PURPOSE: To assess bowel dose-volume relationships for acute patient-reported intestinal symptoms of patients treated with whole-pelvis intensity-modulated radiotherapy (WPRT) for prostate cancer. MATERIALS AND METHODS: Complete data of 415 patients enrolled in a multi institute, prospective trial (#NCT02803086) treated with radical (31%), adjuvant (33%) and salvage (36%) intent at a median dose to pelvic nodes/lymph-nodal area of 53 Gy were available. The most severe changes between baseline and radiotherapy mid-point/end toxicity assessed by Inflammatory Bowel Disease Questionnaire (only Bowel Domain) were considered (ΔIBDQ). The 25th percentile values of these score variations were set as endpoints. DVHs of bowel loops for patients with/without toxicity were compared for each endpoint, having excluded patients with baseline scores <5 (rate ranging between 2% and 7% according to the endpoint): the resulting best dosimetric predictors were combined with selected clinical parameters through multivariate logistic regression (MVA) to derive predictive models. RESULTS: ΔIBDQ ranged between 0.2-1.5 points considering separately each IBDQ symptom. Only four symptoms (IBDQ1 = frequency, IBDQ5 = diarrhea, IBDQ17 = gas passage, IBDQ24 = urgency) showed a median worsening ≥ 1; DVH predicted the risk of worse symptoms for IBDQ5, IBDQ24 and overall Bowel Domain. At multivariable analysis DVHs (best cut-off: V46Gy ≥80 cc) and baseline scores (Odd-Ratio:0.35-0.65) were independently associated to the three end-points. The resulting models were reliable (H&L test: 0.453-0.956), well calibrated (calibration plot: slope = 0.922-1.069, R2 = 0.725-0.875) and moderately discriminative (Area Under the Curve:0.628-0.669). A bootstrap-based validation confirmed their robustness. CONCLUSION: Constraining the bowel loops (V46 < 80 cc) may reduce the risk of several moderate intestinal symptoms, with a much greater impact for patients with lower IBDQ baseline scores.

Ct radiomic features of pancreatic neuroendocrine neoplasms (panNEN) are robust against delineation uncertainty.

PURPOSE: The aim of this study was to quantify the impact of CT delineation uncertainty of pancreatic neuroendocrine neoplasms (panNEN) on Radiomic features (RF). METHODS: Thirty-one previously operated patients were considered. Three expert radiologists contoured panNEN lesions on pre-surgical high-resolution contrast-enhanced CT images and contours were transferred onto pre-contrast CT. Volume agreement was quantified by the DICE index. After images resampling and re-binning, 69 RF were extracted and the impact of inter-observer variability was assessed by Intra-Class Correlation (ICC): ICC > 0.80 was considered as a threshold for "very high" inter-observer agreement. RESULTS: The median volume was 1.3 cc (range: 0.2-110 cc); a satisfactory inter-observer volume agreement was found (mean DICE = 0.78). Only 4 RF showed ICC < 0.80 (0.48-0.73), including asphericity and three RFs (of five) of the neighborhood intensity difference matrix (NID). CONCLUSIONS: The impact of inter-observer variability in delineating panNEN on RF was minimum, with the exception of the NID family and asphericity, showing a moderate agreement. These results support the feasibility of studies aiming to assess CT radiomic biomarkers for panNEN.

Magnetic Resonance, Vendor-independent, Intensity Histogram Analysis Predicting Pathologic Complete Response After Radiochemotherapy of Rectal Cancer.

PURPOSE: The objective of this study is finding an intensity based histogram (IBH) signature to predict pathologic complete response (pCR) probability using only pre-treatment magnetic resonance (MR) and validate it externally in order to create a workflow for the external validation of an MR IBH signature and to apply the model out of the environment where it has been tuned. The impact of pCR and the final predictors on the survival outcome were also evaluated. METHODS AND MATERIALS: Three centers using different MR scanners were involved in this retrospective study. The first center recruited 162 patients for model training, and the second and third centers provided 34 plus 25 patients for external validation. Patients provided written consent. Accrual period was from May 2008 to December 2014. After surgery pathologic response was defined. T2-weighted MR scans acquired before chemoradiation therapy (CRT) were used for analysis addressed on primary lesions. Images were pre-processed using Laplacian of Gaussian (LoG) filter with multiple σ, and first order intensity histogram-based features (kurtosis, skewness, and entropy) were extracted. Features selection was performed using Mann-Whitney test. Tumor staging (cT, cN) was added to build a logistic regression model and predict pCR. Model performance was evaluated with internal and external validation using area under the curve (AUC) of the receiver operator characteristic (ROC) and calibration with Hosmer-Lemeshow test. The linear cross-correlation matrix (Pearson's coefficient) and the variance inflation factor (VIF) were used to check the correlation and the co-linearity among the final predictors. The amount of the information added through the radiomics features was estimated by using the DeLong's test, and the impact of pCR and the final predictors on survival outcomes were evaluated through the Kaplan-Meier curves by using the log-rank test and the multivariate Cox model. RESULTS: Candidate-to-analysis features were skewness (σ = 0.485, P value = .01) and entropy (σ = 0.344, P value < .05). Logistic regression analysis showed as significant covariates cT (P value < .01), skewness-σ = 0.485 (P value = .01), and entropy-σ = 0.344 (P value < .05). Model AUCs were 0.73 (internal) and 0.75 (external). CONCLUSIONS: This MR-based, vendor-independent model can be helpful for predicting pCR probability in locally advanced rectal cancer (LARC) patients only using pre-treatment imaging.

Patient-reported urinary incontinence after radiotherapy for prostate cancer: Quantifying the dose-effect.

BACKGROUND AND PURPOSE: Urinary incontinence following radiotherapy (RT) for prostate cancer (PCa) has a relevant impact on patient's quality of life. The aim of the study was to assess the unknown dose-effect relationship for late patient-reported urinary incontinence (LPRUI). METHODS AND MATERIALS: Patients were enrolled within the multi-centric study DUE01. Clinical and dosimetry data including the prescribed 2Gy equivalent dose (EQD2) were prospectively collected. LPRUI was evaluated through the ICIQ-SF questionnaire filled in by the patients at RT start/end and therefore every 6months. Patients were treated with conventional (74-80Gy, 1.8-2Gy/fr) or moderately hypo-fractionated RT (65-75.2Gy, 2.2-2.7Gy/fr) in 5 fractions/week with intensity-modulated radiotherapy. Six different end-points of 3-year LPRUI, including or not patient's perception (respectively, subjective and objective end-points), were considered. Multivariable logistic models were developed for each end-point. RESULTS: Data of 298 patients were analyzed. The incidence of the most severe end-point (ICIQ-SF>12) was 5.1%. EQD2 calculated with alpha-beta=0.8Gy showed the best performance in fitting data: the risk of LPRUI markedly increased for EQD2>80Gy. Previous abdominal/pelvic surgery and previous TURP were the clinical factors more significantly predictive of LPRUI. Models showed excellent performances in terms of goodness-of-fit and calibration, confirmed by bootstrap-based internal validation. When included in the analyses, baseline symptoms were a major predictor for 5 out of six end-points. CONCLUSIONS: LPRUI after RT for PCa dramatically depends on EQD2 and few clinical factors. Results are consistent with a larger than expected impact of moderate hypo-fractionation on the risk of LPRUI. As expected, baseline symptoms, as captured by ICIQ-SF, are associated to an increased risk of LPRUI.

Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams.

We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth-dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry.

Patient-reported intestinal toxicity from whole pelvis intensity-modulated radiotherapy: First quantification of bowel dose-volume effects.

BACKGROUND AND PURPOSE: Intestinal toxicity is commonly experienced during whole-pelvis intensity-modulated radiotherapy (WPRT) for prostate cancer. The aim of the current study was to assess bowel dose-volume relationships for acute patient-reported intestinal symptoms of patients treated with WPRT for prostate cancer. MATERIALS AND METHODS: Complete data of 206 patients were available; the median dose to pelvic nodes was 51.8Gy (range 50.4-54.4, 1.7-2Gy/fr). Intestinal symptoms were assessed as changes in the Inflammatory Bowel Disease Questionnaire scores relative to the Bowel Domain (IBDQ-B) between baseline and radiotherapy mid-point/end. The 25th percentiles of the most severe worsening from baseline (ΔIBDQ-B) were set as end-points. The impact of bowel loops and sigmoid colon dose-volume/surface parameters as well as selected clinical parameters were investigated using multivariate logistic regression. RESULTS: Analyses were focused on the four questions showing a median ΔIBDQ-B>0. No dose volume/surface parameters were predictive, other than ΔIBDQ5≥3 (loose stools): when grouping patients according to bowel DVHs (high risk: V20>470cc, V30>245cc, V42>110cc; low risk: all the remaining patients), a two-variable model including high-risk DVH-shape (OR: 9.3) and age (protective, OR: 0.94) was assessed. The model showed good calibration (slope: 1.003, R2=0.92) and was found to be robust after bootstrap-based internal validation. CONCLUSIONS: Constraining the bowel loops may reduce the risk of loose stools. The risk is higher for younger patients.

Hematologic Toxicity in Patients Treated With Postprostatectomy Whole-Pelvis Irradiation With Different Intensity Modulated Radiation Therapy Techniques Is Not Negligible and Is Prolonged: Preliminary Results of a Longitudinal, Observational Study.

PURPOSE: To address the thus-far poorly investigated severity and duration of hematologic toxicity from whole-pelvis radiation therapy (WPRT) in a cohort of chemo-naïve patients treated with postprostatectomy radiation therapy including WPRT with different intensity modulated radiation therapy (IMRT) techniques, doses, and fractionations. METHODS AND MATERIALS: This analysis pertains to 125 patients (70 from a pilot study and 55 from an observational protocol) for whom 1 baseline and at least 3 subsequent blood samples (median 6), obtained at irradiation midpoint and end, and thereafter at 3, 6, and 12 months, were available. Patients were treated with adjuvant (n=73) or salvage intent; static-field IMRT (n=19); volumetric modulated arc therapy (n=60) or helical Tomotherapy (n=46); and conventional (n=39) or moderately hypofractionated (median 2.35 Gy per fraction, n=86) regimens. The median 2-Gy equivalent dose (EQD2) to the prostatic bed was 70.4 Gy with a lymph-nodal planning target volume of 50.2 Gy. Clinical and dosimetric data were collected. RESULTS: Both leukopenia and thrombocytopenia were significant (median nadir count 65% and 67% of baseline, respectively), with leukopenia also persisting (1-year median count 75% of baseline). Lymphopenia was the major contributor to the severity and 1-year persistence of leukopenia; all patients developed acute grade ≥1 lymphopenia (61% and 26% grade 2 and ≥3, respectively), whereas 1-year grade ≥2 lymphopenia was still present in 16%. In addition to an independent predictive role of corresponding baseline values, multivariable analyses highlighted that higher EQD2 doses to lymph nodal planning target volume increased risk of acute neutropenia and hypofractionation for acute thrombocytopenia. Of note, patients of older age were at higher risk for acute grade 2 lymphopenia, and interestingly, increased risk of grade >2 lymphopenia for those who smoked at least one year. No role for different IMRT techniques indicated. CONCLUSIONS: Leukopenia and lymphopenia after postprostatectomy WPRT were found to be less negligible and more prolonged than expected. A number of radiation-related and clinical factors favoring hematologic toxicity, whose awareness may be crucial when prescribing WPRT, in particular if concomitant to chemotherapy, were identified.

Dose-volume effects for pelvic bone marrow in predicting hematological toxicity in prostate cancer radiotherapy with pelvic node irradiation.

PURPOSE: To prospectively identify clinical/dosimetric predictors of acute/late hematologic toxicity (HT) in chemo-naÏve patients treated with whole-pelvis radiotherapy (WPRT) for prostate cancer. MATERIAL AND METHODS: Data of 121 patients treated with adjuvant/salvage WPRT were analyzed (static-field IMRT n=19; VMAT/Rapidarc n=57; Tomotherapy n=45). Pelvic bone marrow (BM) was delineated as ilium (IL), lumbosacral, lower and whole pelvis (WP), and the relative DVHs were calculated. HT was graded both according to CTCAE v4.03 and as variation in percentage relative to baseline. Logistic regression was used to analyze association between HT and clinical/DVHs factors. RESULTS: Significant differences (p<0.005) in the DVH of BM volumes between different techniques were found: Tomotherapy was associated with larger volumes receiving low doses (3-20 Gy) and smaller receiving 40-50 Gy. Lower baseline absolute values of WBC, neutrophils and lymphocytes (ALC) predicted acute/late HT (p ⩽ 0.001). Higher BM V40 was associated with higher risk of acute Grade3 (OR=1.018) or late Grade2 lymphopenia (OR=1.005). Two models predicting lymphopenia were developed, both including baseline ALC, and BM WP-V40 (AUC=0.73) and IL-V40+smoking (AUC=0.904) for acute/late respectively. CONCLUSIONS: Specific regions of pelvic BM predicting acute/late lymphopenia, a risk factor for viral infections, were identified. The 2-variable models including specific constraints to BM may help reduce HT.

Accuracy of dose calculation algorithms for static and rotational IMRT of lung cancer: A phantom study.

PURPOSE: To evaluate the dosimetric accuracy of Pencil beam (PB), Anisotropic Analytical Algorithm (AAA) and Collapsed Cone Convolution Superposition (CCCS) in thoracic tumours for various IMRT techniques. METHODS: Step-and-shoot Linac IMRT (IMRT), arc volumetric RapidArc (RA) and Helical Tomotherapy (HT) lung treatments for different clinical situations (mediastinum tumour, single metastasis and multiple metastases) were simulated and calculated with PB/AAA, AAA, CCCS, respectively. Delivery quality assurance plans were first verified in homogeneous media (Cheese phantom and ArcCHECK); then several low-density inhomogeneous phantoms were used: the Multiplug ArcCHECK, the commercial ArcCHECK slightly modified with a low density lung-shape insert and a custom-made slab heterogeneous phantom simulating the thorax region. Absolute doses and planar dose maps were checked to assess the agreement between measured and calculated dose distributions. RESULTS: In total, data referred to 195 point dose measurements and 189 planar measurements were considered. Average point absolute deviations <3% were found for all the delivery techniques/dose algorithms. In small targets completely embedded in very low density media, deviations up to 7-10% and 4-5% were found for PB and AAA/CCCS respectively. Excellent results were found for planar measurements in ArcCHECK configurations, where ≥ 95% of points satisfy the 3%/3 mm acceptance criteria for all the algorithms. CONCLUSIONS: A satisfactory agreement (<2%) between planned and measured doses was generally found for CCCS and AAA, excepting the very critical situation of a small tumour completely embedded in air. A significant dose overestimation (from few to 5-7%) was confirmed for PB in complex inhomogeneous arrangements.