Dose prescription in SBRT for early-stage non-small cell lung cancer: are we all speaking the same language?

INTRODUCTION: Stereotactic body radiation therapy is increasingly used in the treatment of early-stage lung cancers. Guidelines provide indications regarding the constraints to the organs at risk (OARs) and the minimum coverage of the planning target volume but do not suggest optimal dose distribution. Data on dose distribution from the different published series are not comparable due to different prescription modalities and reported dose parameters. METHODS: We conducted a review of the published data on dose prescription, focusing on the role of homogeneity on local tumor control, and present suggestions on how to specify and report the prescriptions to permit comparisons between studies or between cases from different centers. CONCLUSIONS: To identify the dose-prescription modality that better correlates with oncologic outcomes, future studies should guarantee a close uniformity of dose distribution between cases and complete dose parameters reporting for treatment volumes and OARs.

Small field correction factors determination for several active detectors using a Monte Carlo method in the Elekta Axesse linac equipped with circular cones.

A Monte Carlo (MC) method was used to determine small field output correction factors for several active detectors (Exradin A16, Exradin A26, PTW microLion, PTW microDiamond, Exradin W1 and IBA RAZOR) for an Elekta Axesse linac equipped with circular cones. MC model of the linac was built with the GamBet software, using the Penelope code system. The dose-to-water simulation for each cone, ranging from 5 to 30 mm of diameter size, was used to calculate field factors and the results were validated together with Gafchromic EBT3 film. Output factors (OFs) were measured with the active detectors and correction factors were determined using the MC results. The MC simulations agreed with films within 1.2%. OFs measured with Exradin W1 scintillator were in agreement within 0.8% with MC simulations. The Exradin A16 and A26 microchambers under-responded for small fields relative to the MC (-13.1% and -4.6%, respectively). PTW microLion, IBA RAZOR and PTW microDiamond overestimated the output factor for the smallest field (+3.9%, +5.4 and +7.1%, respectively). The present study pointed out that it is crucial to apply the appropriate correction factors in order to provide accurate measurements in small beams geometry. The results showed that the Exradin W1 can be used for very small field dosimetry without correction factors, which shall be contrariwise employed for other detectors.

Inclusion of heart substructures in the optimization process of volumetric modulated arc therapy techniques may reduce the risk of heart disease in Hodgkin's lymphoma patients.

BACKGROUND AND PURPOSE: Radiotherapy is an effective treatment for Hodgkin's lymphoma (HL), but increases the risk of long term complications as cardiac events and second cancers. This study aimed to reduce the risk of cardiovascular events through an optimization of the dose distribution on heart substructures in mediastinal HL patients with the adoption of different volumetric modulated arc therapy (VMAT) techniques, while maintaining the same risk of second cancer induction on lungs and breasts. MATERIALS AND METHODS: Thirty patients (15 males and 15 females, 15 bulky lesions) treated between 2012 and 2017 at our institution were selected. Disease extent was mediastinum plus neck (n = 10), mediastinum plus unilateral axilla (n = 10) and mediastinum alone (n = 10). Lungs, breasts, whole heart and sub-structures (coronary arteries, valves and chambers) were contoured as organs at risk and included in the optimization process. A "first-generation" multi-arc butterfly VMAT (B-VMAT) planning solution was compared to a full-arc butterfly VMAT (FaB-VMAT) approach, consisting of a full arc plus a non-coplanar arc. Lifetime attributable risk (LAR) of second breast and lung cancer and relative risk (RR) of coronary artery disease (CAD) and chronic heart failure (CHF) were estimated. RESULTS: FaB-VMAT resulted in lower mean dose to whole heart (7.6 vs 6.9 Gy, p = 0.003), all coronary arteries (16.1 vs 13.5 Gy, p < 0.001), left ventricle (4.2 vs 3.4 Gy, p = 0.007) and in lower V20Gy to the lungs (15% vs 14%, p = 0.008). A significant lower RR for CAD and CHF was observed for FaB-VMAT. The risk of second breast and lung cancer was comparable between the two solutions, with the exception of female patients with mediastinal bulky involvement, where B-VMAT resulted in lower mean dose (2.8 vs 3.5 Gy, p = 0.03) and V4Gy (22% vs 16%, 0.04) to breasts, with a significant reduction in LAR (p = 0.03). CONCLUSIONS: FaB-VMAT significantly decreased the RR for CAD and CHF compared to B-VMAT, with almost the same overall risk of lung and breast cancer induction. These results are influenced by the different anatomical presentations, supporting the need for an individualized approach.

Volumetric modulated arc therapy (VMAT) in the treatment of esophageal cancer patients.

The aim of the study is to evaluate feasibility, safety, toxicity profile, and dosimetric results of volumetric modulated arc therapy (VMAT) to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients. A total of 68 patients were treated with VMAT between March 2014 and March 2018 (44% vs 56% for definitive and neoadjuvant settings, respectively). Dose prescription differed depending on the clinical scenario (54-60 Gy in 30 fractions for definitive treatments; 41.4/45 Gy in 23-25 fractions in the pre-operative setting). Most of the patients were given concurrent chemotherapy. Two coplanar and one non-coplanar arcs were employed for VMAT delivery. Treatment was generally well tolerated. Acute toxicity was generally mild. In patients treated with definitive intent, ≥ G3 toxicities were observed for esophagitis (30%), anorexia (26.7%), fatigue (26.7%), nausea (6.7%), and vomiting (3.3%). In patients treated within a neoadjuvant approach, ≥ G3 anorexia (21%), esophagitis (15.8%), fatigue (13.3%), nausea (5.3%), and vomiting (2.6%) were observed. Dosimetric results were consistent in term of both target coverage and normal tissue sparing. In conclusion, VMAT proved to be a feasible, safe, and effective strategy to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients.

Dose to Pelvic Bone Marrow Defined with FDG-PET Predicts for Hematologic Nadirs in Anal Cancer Patients Treated with Concurrent Chemo-radiation.

PURPOSE: To investigate whether irradiated volume of pelvic active bone marrow (ACTBM) may predict decreased blood cells nadirs in anal cancer patients undergoing concurrent chemo-radiation. METHODS: Forty-four patients were analyzed and pelvic active bone marrow (ACTBM) was characterized employing 18FDG-PET. Dosimetric parameters on dose-volume histograms were correlated to nadirs with generalized linear modeling. RESULTS: ACTBM mean dose was significantly correlated to white blood cell (ß = -1.338; 95%CI: -2.455/-0.221; p = 0.020), absolute neutrophil count (ß = -1.651; 95%CI: -3.284/-0.183; p = 0.048), and platelets (ß = -0.031; 95%CI: -0.057/-0.004; p = 0.024) nadirs. Other dosimetric parameters were found to be correlated (ACTBM-V10,-V20,-V30and-V40). CONCLUSIONS: 18FDG-PET is able to define active bone marrow and may predict for decreased blood cells count nadirs.

Variability of clinical target volume delineation for rectal cancer patients planned for neoadjuvant radiotherapy with the aid of the platform Anatom-e.

OBJECTIVE: Delineation of treatment volumes is a major source of uncertainties in radiotherapy (RT). This is also true for rectal cancer patients undergoing neoadjuvant RT, with a potential impact on treatment quality. We investigated the role of the digital platform Anatom-e (Anatom-e Information Sytems Ltd., Houston, Texas) in increasing the compliance to follow a specific treatment protocol in a multicentric setting. MATERIALS AND METHODS: Two clinical cases of locally advanced rectal cancer were chosen. Participants were instructed to follow the 2009 Radiation Therapy Oncology Group consensus atlas and asked to manually segment clinical target volumes (CTVs), for both patient 1 and 2, on day 1 with and without the use of Anatom-e. After one week (day 2), the same radiation oncologist contoured again, with and without Anatom-e, the same CT series. Intraobserver (Intra-OV) and interobserver (Inter-OV) variability were evaluated with the Dice similarity coefficient (DSC), the Hausdorff distance (HD) and mean distance to agreement (MDA). RESULTS: For clinical case 1, no significant difference was found for Intra-OV and Inter-OV. For clinical case 2, no significant difference was found for Intra-OV but a statistically significant difference was found for Inter-OV in DSC when using or not the platform. Mean DCS was 0.65 (SD: ±0.64; range: 0.58-0.79) for day 1 vs reference volume without Anatom-e and 0.72 (SD: ±0.39; range: 0.67-0.77) (p = 0.03) with it. Mean MDA was lower with Anatom-e (3.61; SD: ±1.33; range: 2.85-4.78) than without (4.14; SD: ±2.97; range: 2.18-5.21), with no statistical significance (p = 0.21) The use of Anatom-e decreased the SD from 2.97 to 1.33. Mean HD was lower with Anatom-e (26.06; SD: ±2.05; range: 24.08-32.62), with no statistical significance (p = 0.14) compared to that without (31.39; SD: ±1.31; range: 26.14-48.72). CONCLUSIONS: The use of Anatom-e decreased the Inter-OV in the CTV delineation process for locally advanced rectal cancer with complex disease presentation planned for neoadjuvant RT. This system may be potentially helpful in increasing the compliance to follow shared guidelines and protocols.

Plan optimization for mediastinal radiotherapy: Estimation of coronary arteries motion with ECG-gated cardiac imaging and creation of compensatory expansion margins.

BACKGROUND AND PURPOSE: Inadvertent heart and coronary arteries (CA) irradiation may increase the risk of coronary artery disease (CAD) in patients receiving thoracic irradiation. To date, the entity of cardiac-related CA displacement and the possible margins to be used for planning organs at risk volume (PRV) have been poorly described. Aim of this study was to quantify CA displacement and to estimate PRV through the use of ECG-gated computed tomography (CT) scans. MATERIAL AND METHODS: Eight patients received an ECG-gated intravenous contrast enhanced CT for non-cancer related reasons. Nine data sets were reconstructed over the entire R-R cycle with a dedicated retrospective algorithm and the following structures were delineated: Left main trunk (LM), left anterior descending (LAD), left circumflex (CX) and right coronary artery (RCA). CA displacements across the different cardiac phases were evaluated in left-right (X), cranio-caudal (Y) and anteroposterior (Z) directions using the McKenzie-van Herk formula (1.3 * Σ + 0.5 * σ). RESULTS: The following CA displacements were found in X, Y and Z coordinates: 3.6, 2.7 and 2.7 mm for LMT, respectively; 2.6, 5.0 and 6.8 mm for LAD, respectively; 3.5, 4.5 and 3.7 mm for CX, respectively; 3.6, 4.6 and 6.9 mm for RCA, respectively. Based on the mean displacements, we created a PRV of 3 mm for LM, 4 mm for CX and 5 mm for LAD and RCA. CONCLUSION: CA showed relevant displacements over the heart cycle, suggesting the need for a specific PRV margin to accurately estimate the dose received by these structures and optimize the planning process.

Evaluation of a commercial automatic treatment planning system for liver stereotactic body radiation therapy treatments.

PURPOSE: Automated treatment planning is a new frontier in radiotherapy. The Auto-Planning module of the Pinnacle3 treatment planning system (TPS) was evaluated for liver stereotactic body radiation therapy treatments. METHODS: Ten cases were included in the study. Six plans were generated for each case by four medical physics experts. The first two planned with Pinnacle TPS, both with manual module (MP) and Auto-Planning one (AP). The other two physicists generated two plans with Monaco TPS (VM). Treatment plan comparisons were then carried on the various dosimetric parameters of target and organs at risk, monitor units, number of segments, plan complexity metrics and human resource planning time. The user dependency of Auto-Planning was also tested and the plans were evaluated by a trained physician. RESULTS: Statistically significant differences (Anova test) were observed for spinal cord doses, plan average beam irregularity, number of segments, monitor units and human planning time. The Fisher-Hayter test applied to these parameters showed significant statistical differences between AP e MP for spinal cord doses and human planning time; between MP and VM for monitor units, number of segments and plan irregularity; for all those between AP and VM. The two plans created by different planners with AP were similar to each other. CONCLUSIONS: The plans created with Auto-Planning were comparable to the manually generated plans. The time saved in planning enables the planner to commit more resources to more complex cases. The independence of the planner enables to standardize plan quality.

Evaluation of dose recalculation vs dose deformation in a commercial platform for deformable image registration with a computational phantom.

Deformable image registration (DIR) is an important tool for mapping both dose and contours of a new set of planning images when recurrent, that is, adaptive radiotherapy, or further treatment, that is, re-treatment, is required. The aim of this study was to evaluate the need for plan recalculation in deformed anatomies and to develop a reliable workflow for validating the DIR algorithm to be applied to dose warping such as dose accumulation (DA) for adaptive radiation therapy, and dose summation (DS) in the case of re-treatment. A set of 3 computational phantoms was developed to validate the application of B-Spline-based registrations for dose mapping among the various computed tomography image data sets. Two different versions were defined for each phantom to simulate clinical needs: adaptive radiotherapy and re-treatment; a DIR was performed to obtain a displacement vector field (DVF) for dose applications. Comparison of calculated and deformed doses was carried out by means of known markers inside the virtual phantoms. The differences were evaluated using a 3% dose index as acceptance criteria. A paired Wilcoxon signed-rank test was carried out to test the statistical significance of differences within the markers. Significant differences were only observed for the deformed dose in the DA test; no significant differences were observed for recalculated dose values in the DA and DS tests. The dose index is in accordance with these results. The warping dose process obtained by registering various sets of images was validated; a recalculation approach seems to be more accurate for DA purposes and image-guided adaptive radiation therapy (IGART) applications.

Incorporating 18FDG-PET-defined pelvic active bone marrow in the automatic treatment planning process of anal cancer patients undergoing chemo-radiation.

BACKGROUND: To investigate whether the incorporation of 18FDG-PET into the automatic treatment planning process may be able to decrease the dose to active bone marrow (BM) for locally advanced anal cancer patients undergoing concurrent chemo-radiation (CHT-RT). METHODS: Ten patients with locally advanced anal cancer were selected. Bone marrow within the pelvis was outlined as the whole outer contour of pelvic bones or employing 18FDG-PET to identify active BM within osseous structures. Four treatment planning solutions were employed with different automatic optimization approaches toward bone marrow. Plan A used iliac crests for optimization as per RTOG 05-29 trial; plan B accounted for all pelvic BM as outlined by the outer surface of external osseous structures; plan C took into account both active and inactive BM as defined using 18FDG-PET; plan D accounted only for the active BM subregions outlined with 18FDG-PET. Dose received by active bone marrow within the pelvic (ACTPBM) and in different subregions such as lumbar-sacral (ACTLSBM), iliac (ACTIBM) and lower pelvis (ACTLPBM) bone marrow was analyzed. RESULTS: A significant difference was found for ACTPBM in terms of Dmean (p = 0.014) V20 (p = 0.015), V25 (p = 0.030), V30 (p = 0.020), V35 (p = 0.010) between Plan A and other plans. With respect to specific subsites, a significant difference was found for ACTLSBM in terms of V30 (p = 0.020)), V35 (p = 0.010), V40 (p = 0.050) between Plan A and other solutions. No significant difference was found with respect to the investigated parameters between Plan B,C and D. No significant dosimetric differences were found for ACTLSPBM and ACTIBM and inactive BM subregions within the pelvis between any plan solution. CONCLUSIONS: Accounting for pelvic BM as a whole compared to iliac crests is able to decrease the dose to active bone marrow during the planning process of anal cancer patients treated with intensity-modulated radiotherapy. The same degree of reduction may be achieved optimizing on bone marrow either defined using the outer bone contour or through 18FDG-PET imaging. The subset of patients with a benefit in terms of dose reduction to active BM through the inclusion of 18FDG-PET in the planning process needs further investigation.

No differences in radiological changes after 3D conformal vs VMAT-based stereotactic radiotherapy for early stage non-small cell lung cancer.

OBJECTIVE: To compare patterns of acute and late radiological lung injury following either 3D conformal or image-guided volumetric modulated arc therapy stereotactic radiotherapy for Stage I non-small-cell lung cancer. METHODS: We included 148 patients from a prospective mono-institutional stereotactic body radiation therapy (SBRT) series (time interval 2004-2014), treated with prescription BED10 Gy (at 80%) in the range 100-120 Gy. The first 95 patients (2004-2010) were planned with 3D-CRT, with a stereotactic body frame. The second cohort (2010-2014) included 53 patients, planned with volumetric IMRT on a smaller planning target volume generated from a patient's specific internal target volume, with a frameless approach through cone-beam CT guidance. Acute and late radiological modifications were scored based on modified Kimura's and Koenig's classifications, respectively. RESULTS: Median follow-up time was 20.5 months. The incidence of acute radiological changes was superimposable between the groups: increased density was observed in 68.4 and 64.2% of patients for 3D-CRT and VMAT, respectively, and patchy ground glass opacity in 23.7 and 24.5%, respectively; diffuse ground glass opacity was 2.6 vs 9.4%, respectively, and patchy consolidation 2.6 vs 1.9%, respectively. Late changes occurred in approximately 60% of patients: modified conventional pattern was the most frequent modification (25 vs 32.6%, respectively); other patterns were less common (mass-like 19.6 vs 17.4%, and scar-like 13 vs 10.9%, respectively). CONCLUSION: Results of the present study indicate that the pattern of radiological lung changes following SBRT for peripheral early stage non-small-cell lung cancer is not influenced by the different techniques used for planning and delivery. Advances in knowledge: This comparative observational study shows that smaller margins, image guidance and most importantly dose distribution do not change the pattern of radiological injury after lung SBRT; the same scoring system can be used, and expected incidence is similar.

Hematologic toxicity in anal cancer patients during combined chemo-radiation: a radiation oncologist perspective.

INTRODUCTION: Hematologic toxicity is an important side effect occurring in patients affected with anal cancer, undergoing combined radio-chemotherapy, with consistent clinical meaningfulness. Areas covered: Since more than a half of bone marrow is comprised within the pelvic region, the radiation dose received by this functional compartment is crucial. Modern imaging modalities may provide a useful tool to identify bone marrow and new delivery technology may enhance the radiation oncologist's possibility to selectively spare these structures, potentially decreasing acute hematologic toxicity profile in this setting. Expert commentary: Correlation between dose to pelvic structures and acute hematologic toxicity has been studied in several oncological settings, mainly on a retrospective frame. Different dose metrics were found to be correlated including mean doses and different points within the dose-volume histogram ranging from low to medium-high doses. Several imaging modalities were used to identify bone marrow both morphological and functional. Several clinical endpoints were used. In general, accounting for bone marrow during the treatment planning process may be important to decrease the acute hematologic toxicity profile during concurrent chemo-radiation in anal cancer patients. The most appropriate strategy to address this issue need further investigation and deserve validation in a prospective clinical framework.

Lumbar-sacral bone marrow dose modeling for acute hematological toxicity in anal cancer patients treated with concurrent chemo-radiation.

The aim of the study was to model acute hematologic toxicity (HT) and dose to pelvic osseous structures in anal cancer patients treated with definitive chemo-radiation (CT-RT). A total of 53 patients receiving CT-RT were analyzed. Pelvic bone marrow and corresponding subsites were contoured: ilium, lower pelvis and lumbosacral spine (LSBM). Dose-volume histograms points and mean doses were collected. Logistic regression was performed to correlate dosimetric parameters and ≥G3 HT as endpoint. Normal tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression showed a significant correlation between LSBM-mean dose and ≥G3 leukopenia (ß coefficient 0.122; p = 0.030; 95% CI 0.012-0.233). According to NTCP modeling, the predicted HT probability had the following parameters: TD50: 37.5 Gy, γ 50: 1.15, m: 0.347. For node positive patients, TD50: 35.2 Gy, γ 50: 2.27, m: 0.176 were found. Node positive patients had significantly higher PBM-V15 (Mean 81.1 vs. 86.7%; p = 0.04), -V20 (Mean 72.7 vs. 79.9%; p = 0.01) and V30 (Mean 50.2 vs. 57.3%; p = 0.03). Patients with a mean LSBM dose >32 Gy had a 1.81 (95% CI 0.81-4.0) relative risk to develop ≥G3 leukopenia. For node positive patients, those risks were 2.67 (95% CI 0.71-10). LKB modeling seems to suggest that LSBM-mean dose should be kept below 32 Gy to minimize ≥G3 HT in anal cancer patients treated with IMRT and concurrent chemotherapy. The contribution of LSBM dose in the development of HT above 25 Gy seems steeper in node positive patients.

Stereotactic ablative radiotherapy in the treatment of hepatocellular carcinoma >3 cm.

Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable results to other local therapies. For lesions larger than 3 cm, no definitive standard treatment is present and several options are available. We retrospectively review local control (LC) and survival results of SABR in patients with HCC lesions >3 cm. Between 2012 and 2015, we treated 29 patients (39 lesions) having histological or radiological diagnosis of HCC and at least one lesion sized >3 cm. Patients were prescribed 36-48 Gy in 3-5 fractions (mainly 16 Gy × 3 fractions or 8 Gy × 5 fractions), in 3-5 consecutive days. A total of 15 lesions (52 %) had complete, while 10 (34 %) had partial remission; 3 (11 %) had a stable disease. Mean time for CR achievement was 5.8 months (range 1-17). One- and two-year actuarial LC was 100 %. Moreover, 1- and 2-year progression-free (PFS), cancer-specific and overall survival were 57.9 % [standard error (SE) 0.09; 95 % CI 36.9-74.2] and 41.2 % (SE 0.12; 95 % CI 17.7-63.5), 80.7 % (SE 0.08; 95 % CI 59.6-91.5) and 63.3 % (SE 0.11; 95 % CI 38.4-80.3), 71.7 % (SE 0.08; 95 % CI 51.2-84.7) and 56.2 % (SE 0.10; 95 % CI 33.8-73.6). On multivariate analysis, achieving a CR within the target lesion had a borderline significance with respect to PFS (HR 0.83; SE = 0.014; z -1.15; p = 0.095; 95 % CI 0.71-7.45). Time between HCC diagnosis and SABR delivery (< vs >12 months) was significantly correlated with OS (HR 16.5; SE 21.5; z = 2.14; p = 0.032; 95 % CI 1.27-213.3) as CLIP score (score: 0-1 vs 2) (HR 5.6; SE 4.6; z = 2.10; p = 0.036; 95 % CI 1.11-27.8). A total of 6 major toxic events (G3-G4) were recorded (20 %). In 2 patients (6 %), a radiation-induced liver disease was seen. In conclusion, SABR provided LC and survival rates comparable to other local therapies for patients with HCC lesion sized >3 cm, with acceptable toxicity profile.

Hypofractionation with no boost after breast conservation in early-stage breast cancer patients.

The aim of this study was to evaluate local control, survival and toxicity profile of a consecutive cohort of early-stage breast cancer (EBC) patients treated with adjuvant hypofractionated radiotherapy (HF) with no boost delivered to the lumpectomy cavity, after breast-conserving surgery (BCS). Between 2005 and 2015, a total of 493 women affected with EBC were treated with HF (46 Gy/20 fractions or 40.05 Gy/15 fractions) to the whole breast without boost to tumor bed, because of age and/or favorable tumor characteristics. The primary endpoint was 5-year actuarial local control (LC); secondary endpoints included survival, toxicity profile and cosmesis. Median follow-up was 57 months (range 6-124). Actuarial 5-year overall, cancer-specific, disease-free survival and LC were 96.3, 98.9, 97.8 and 98.6 %, respectively. On multivariate analysis, tumor stage (T1 vs. T2) and hormonal status (positive vs. negative estrogen receptors) were significantly correlated with LC. Only 2 % of patients experienced ≥G3 acute skin toxicity. Late toxicity was mild with only 1 case of G3 fibrosis. Most of the patients (95 %) had good-excellent cosmetic results. HF to the whole breast with no boost delivered to the tumor bed is a safe and effective option for a population of low-risk breast cancer patients after BCS, with excellent 5-year LC, mild toxicity profile and promising cosmetic outcome. A subgroup of patients with larger tumors and/or with no estrogen receptor expression may potentially benefit from treatment intensification with a boost dose to the lumpectomy cavity.

Dose to specific subregions of pelvic bone marrow defined with FDG-PET as a predictor of hematologic nadirs during concomitant chemoradiation in anal cancer patients.

To test the hypothesis that irradiated volume of specific subregions of pelvic active bone marrow as detected by (18)FDG-PET may be a predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation, we analyzed 44 patients submitted to IMRT and concurrent chemotherapy. Several bony structures were defined: pelvic and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. Active BM was characterized employing (18)FDG-PET and characterized in all subregions as the volume having standard uptake values (SUVs) higher than SUVmean. All other regions were defined as inactive BM. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin (Hb) and platelet (Plt) nadirs. Generalized linear modeling was used to find correlations between dosimetric variables and blood cells nadirs. WBC nadir was significantly correlated with LSBM mean dose (ß = -1.852; 95 % CI -3.205/-0.500; p = 0.009), V10 (ß = -2.153; 95 % CI -4.263/-0.721; p = 0.002), V20 (ß = -2.081; 95 % CI -4.880/-0.112; p = 0.003), V30 (ß = -1.971; 95 % CI -4.748/-0.090; p = 0.023) and IBM V10 (ß = -0.073; 95 % CI -0.106/-0.023; p = 0.016). ANC nadir found to be significantly associated with LSBM V10 (ß = -1.878; 95 % CI -4.799/-0.643; p = 0.025), V20 (ß = -1.765; 95 % CI -4.050/-0.613; p = 0.030) and IBM V10 (ß = -0.039; 95 % CI -0.066/-0.010; p = 0.027). Borderline significance was found for correlation between Plt nadir and LSBM V30 (ß = -0.056; 95 % CI -2.748/-0.187; p = 0.060), V40 (ß = -0.059; 95 % CI -3.112/-0.150; p = 0.060) and IBM V30 (ß = -0.028; 95 % CI -0.074/-0.023; p = 0.056). No inactive BM subsites were found to be correlated with any blood cell nadir. (18)FDG-PET is able to define active bone marrow within pelvic osseous structures. LSBM is the strongest predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation.

Evaluation of various approaches for assessing dose indicators and patient organ doses resulting from radiotherapy cone-beam CT.

PURPOSE: The aim of this study was to evaluate various approaches for assessing patient organ doses resulting from radiotherapy cone-beam CT (CBCT), by the use of thermoluminescent dosimeter (TLD) measurements in anthropomorphic phantoms, a Monte Carlo based dose calculation software, and different dose indicators as presently defined. METHODS: Dose evaluations were performed on a CBCT Elekta XVI (Elekta, Crawley, UK) for different protocols and anatomical regions. The first part of the study focuses on using pcxmc software (pcxmc 2.0, STUK, Helsinki, Finland) for calculating organ doses, adapting the input parameters to simulate the exposure geometry, and beam dose distribution in an appropriate way. The calculated doses were compared to readouts of TLDs placed in an anthropomorphic Rando phantom. After this validation, the software was used for analyzing organ dose variability associated with patients' differences in size and gender. At the same time, various dose indicators were evaluated: kerma area product (KAP), cumulative air-kerma at the isocenter (Kair), cone-beam dose index, and central cumulative dose. The latter was evaluated in a single phantom and in a stack of three adjacent computed tomography dose index phantoms. Based on the different dose indicators, a set of coefficients was calculated to estimate organ doses for a range of patient morphologies, using their equivalent diameters. RESULTS: Maximum organ doses were about 1 mGy for head and neck and 25 mGy for chest and pelvis protocols. The differences between pcxmc and TLDs doses were generally below 10% for organs within the field of view and approximately 15% for organs at the boundaries of the radiation beam. When considering patient size and gender variability, differences in organ doses up to 40% were observed especially in the pelvic region; for the organs in the thorax, the maximum differences ranged between 20% and 30%. Phantom dose indexes provided better correlation with organ doses than Kair and KAP, with average ratios ranging between 0.9 and 1.1 and variations for different organs and protocols below 20%. The triple phantom setup allowed us to take into account scatter dose contributions, but nonetheless, the correlation with the evaluated organ doses was not improved with this method. CONCLUSIONS: The simulation of rotational geometry and of asymmetric beam distribution by means of pcxmc 2.0 enabled us to determine patient organ doses depending on weight, height and gender. Alternatively, the measurement of an in phantom dose indicator combined with proper correction coefficients can be a useful tool for a first dose estimation of in-field organs. The data and coefficients provided in this study can be applied to any patient undergoing a scan by an Elekta XVI equipment.

Lung stereotactic ablative body radiotherapy: A large scale multi-institutional planning comparison for interpreting results of multi-institutional studies.

PURPOSE: A large-scale multi-institutional planning comparison on lung cancer SABR is presented with the aim of investigating possible criticism in carrying out retrospective multicentre data analysis from a dosimetric perspective. METHODS: Five CT series were sent to the participants. The dose prescription to PTV was 54Gy in 3 fractions of 18Gy. The plans were compared in terms of PTV-gEUD2 (generalized Equivalent Uniform Dose equivalent to 2Gy), mean dose to PTV, Homogeneity Index (PTV-HI), Conformity Index (PTV-CI) and Gradient Index (PTV-GI). We calculated the maximum dose for each OAR (organ at risk) considered as well as the MLD2 (mean lung dose equivalent to 2Gy). The data were stratified according to expertise and technology. RESULTS: Twenty-six centers equipped with Linacs, 3DCRT (4% - 1 center), static IMRT (8% - 2 centers), VMAT (76% - 20 centers), CyberKnife (4% - 1 center), and Tomotherapy (8% - 2 centers) collaborated. Significant PTV-gEUD2 differences were observed (range: 105-161Gy); mean-PTV dose, PTV-HI, PTV-CI, and PTV-GI were, respectively, 56.8±3.4Gy, 14.2±10.1%, 0.70±0.15, and 4.9±1.9. Significant correlations for PTV-gEUD2 versus PTV-HI, and MLD2 versus PTV-GI, were observed. CONCLUSIONS: The differences in terms of PTV-gEUD2 may suggest the inclusion of PTV-gEUD2 calculation for retrospective data inter-comparison.

Early-stage Node-negative (T1-T2N0) Anal Cancer Treated with Simultaneous Integrated Boost Radiotherapy and Concurrent Chemotherapy.

AIM: To report clinical outcomes of a consecutive series of patients with early-stage (T1-T1N0) anal cancer treated with intensity-modulated radiotherapy (IMRT) and a simultaneous integrated boost (SIB) approach similarly to the RTOG 05-29 trial. PATIENTS AND METHODS: A cohort of 43 patients underwent SIB-IMRT employing a schedule consisting of 50.4 Gy/28 fractions to the gross tumor volume and 42 Gy/28 fractions to the elective nodal volumes for cT1N0 cases, and 54 Gy/30 fractions and 45 Gy/30 fractions to the same volumes for cT2N0 cases. Chemotherapy was administered concurrently following Nigro's regimen. The primary endpoint was colostomy-free survival (CFS). Secondary endpoints were locoregional control (LRC), disease-free (DFS), cancer-specific (CSS) and overall (OS) survival. RESULTS: Median follow-up was 39.7 months. The actuarial 3-year CFS was 79.4% [95% confidence interval (CI)=61.4-89.7%]. Actuarial 3-year OS and CSS were 90.8% (95% CI=74.1-96.9%) and 93.8% (95% CI=77.3-98.4%), while DFS was 75.5% (95% CI=56.4-87.1%). Actuarial 3-year LRC was 86.1% (95% CI=69.6-94%). On multivariate analysis, tumor size >3 cm showed a trend towards significance in predicting CFS [hazard ratio (HR)=8.6, 95% CI=84.7-88.1%; p=0.069]. Maximum detected adverse events included: skin (G3): 18%; gastrointestinal tract (G2): 67%; genitourinary tract (G3): 3%; genitalia (G2): 30%; anemia (G2): 7%; leukopenia (G3): 26%, leukopenia (G4):7%; neutropenia (G3): 15%; neutropenia (G4): 12%; thrombocytopenia (G3): 9%. CONCLUSION: Our clinical results support the use of SIB-IMRT in the combined modality treatment of patients with anal cancer.

Locally Advanced (T3-T4 or N+) Anal Cancer Treated with Simultaneous Integrated Boost Radiotherapy and Concurrent Chemotherapy.

AIM: To report on clinical outcomes of a consecutive series of locally advanced (T3-T4N0-N3) anal cancer patients treated with intensity-modulated radiotherapy (IMRT) and a simultaneous integrated boost (SIB) approach similarly to the RTOG 05-29 trial. PATIENTS AND METHODS: A cohort of 45 patients underwent SIB-IMRT employing a schedule consisting of 54 Gy/30 fractions to the macroscopic anal planning target volume (PTV), while clinical nodes were prescribed 50.4 Gy/30 fractions if sized ≤3 cm or 54 Gy/30 fractions if >3 cm. Elective nodal PTV was prescribed 45 Gy/30 fractions. Chemotherapy was administered concurrently following the Nigro regimen. Primary end-point was colostomy-free survival (CFS). Secondary end-points were locoregional control (LRC), disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS: Median follow-up was 39.7 months. The actuarial 3-year CFS was 63.4 % (95% confidence interval (CI=44.8-77.1%). Actuarial 3-year OS and CSS were 67.7% (95%CI=48.7-80.9%) and 72.9% (95%CI=53.8-85.1%), while DFS was 55.8% (95%CI=37.5.4-70.7%). Actuarial 3-year LRC was 74.1% (95%CI=56.7-85.4%). On multivariate analysis, male sex (hazard ratio (HR)=10.9; p=0.004; 95%CI=2.2-55.5%) had a significant impact on CFS, while higher clinical stage (Stage IIIB vs. others) had borderline significance (HR=2.7; p=0.062; 95%CI=1.8-5.9%). A shorter package time (HR=0.94; p=0.007; 95%CI=0.91-0.98%) predicted for higher CFS. Maximum detected events included: skin (G3): 13%; gastrointestinal (GI) (G3): 13%; genitourinary (GU) (G2): 38%; genitalia (G2): 45%; anemia (G2): 4%; leukopenia (G3): 24%, (G4):7%; neutropenia (G3): 16%; (G4): 11%; thrombocytopenia (G3): 9%, (G4): 2%. CONCLUSION: Our clinical results support the use of SIB-IMRT in the combined modality treatment of locally advanced anal cancer patients.