Gross Tumor Volume Dose Research Articles

Long-Term Patient-Reported Quality of Life and Functional Outcomes After Chemoradiation Using Intensity Modulated Radiotherapy for Anal Cancer

Few studies have long-term follow-up assessing patient-reported outcomes (PROs) after intensity-modulated radiation therapy (IMRT)-based chemoradiation (CRT) for squamous cell carcinoma of the anus (SCCA). There is poor agreement between physician-graded toxicity and PROs regarding quality of life (QOL) in patients with SCCA. Therefore, we surveyed SCCA survivors ≥ 2 years out from CRT with validated PRO instruments assessing bowel, bladder, and sexual function.We identified 248 patients with SCCA treated with definitive IMRT-based CRT at a large tertiary cancer center from 2010-2018, who were alive and without recurrence. Patients were asked to complete five PRO instruments: Fecal Incontinence QOL Scale (FIQOL), Low Anterior Resection Syndrome Score (LARS), International Consultation on Incontinence Questionnaire (ICIQ), male and female lower urinary tract symptoms (MLUTS and FLUTS, respectively), International Index of Erectile Function (IIEF), and Female Sexual Function Index (FSFI). FIQOL, LARS, IIEF, and FSFI scores were dichotomized and logistic regression used to identify predictors of QOL scores.One hundred eight (44%) patients completed the PROs. Respondents' median [interquartile range, (IQR)] age was 66 [59-72] years, 80% were female, and 95% were white. Median [IQR] gross tumor volume (GTV) was 45 [27-71] cc; dose to GTV was 50 Gray (Gy), 54 Gy and 58 Gy in 25%, 53%, and 22%, respectively. Median [IQR] time from CRT was 51 [37-84] months. Median [IQR] FIQOL score was 14.3/20 [11.2-16.1]; higher is better. Larger GTV size (OR 0.99; P = 0.03) was associated with lower FIQOL score. Sixty-one (56%) patients met major LARS criteria. There was a trend towards a higher incidence of major LARS with GTV dose ≥ 54 Gy (OR 2.39; P = 0.08). Men had median [IQR] ICIQ MLUTS voiding and incontinence scores of 5/20 [2-6] and 1/24 [1-3], respectively. Women had median [IQR] ICIQ FLUTS voiding and incontinence scores of 1/12 [1-3] and 5/20 [3-8], respectively; higher is worse. Fifty-nine (55%) patients reported being sexually active in the last month. Men had a median [IQR] IIEF score of 14/25 [6-19]; higher is better. Only age (OR 1.17; P = 0.04) was significantly associated with IIEF ≤ 11 (moderate or severe ED). Women had a median [IQR] FSFI score of 20.2/26 [13.6-24.9]; higher is better. Age < 65 was associated with sexual dysfunction, defined as FSFI < 26.55 (OR, 5.5; P = 0.04). Forty (37%) patients disagreed or strongly disagreed that they were prepared for long-term side effects. Seventy (65%) patients agreed or strongly agreed that educational materials would have been helpful.SCCA survivors experience significant long-term bowel and sexual toxicities from modern CRT. Larger tumors and higher RT doses may be associated with worse function. Interventions to reduce toxicities and improve patient education are needed.

Conebeam CT-Guided MLC-Based GRID Therapy for Very Large Bulky Masses

To evaluate the feasibility, safety and efficacy of conebeam CT-guided MLC-based GRID therapy as a same day treatment procedure for large bulky masses.Twenty-eight patients (12 head and neck, 6 pelvis muscle, 3 breast, 2 chest, 2 liver, 2 para-spinal mass and 1 right arm) with large tumors (range 6.5-13.0 cm) tumors were planned and treated using MLC-based 3D-GRID therapy on the same day as CT-simulation. Utilizing an in-house MLC algorithm, 120 Millennium leaves were fitted to gross tumor volume (GTV) to generate 1 cm diameter holes and 2 cm center-to-center distance (at isocenter). For a single-dose of 15 Gy, 3D MLC-based GRID plans were generated using 4 to 6 coplanar crossfire gantry angles at 60o spacing for differentially-weighted 6 and/or 10MV beams with advanced dose calculation algorithm, generating sieve-like dose channeling without post-processing the GRID-GTV contour-allowing for same day treatment. Dosimetric parameters evaluated included: peak-to-valley dose ratio (PVDR) = GTVD10%/GTVD90%, GTVD50%, mean GTV dose, skin dose and maximal dose to immediately adjacent critical organs. Treatment planning and delivery times and patient set up accuracy was recorded.MLC-GRID plans showed excellent dose parameters with mean GTVD50% and mean GTV of 15 Gy being 7.6 ± 0.5 Gy (range 6.6-8.5 Gy) and 7.8 ± 0.4 Gy (range 7.2-8.9 Gy), respectively. Average PVDR was 3.1 ± 0.6 (range 2.7-4.6). Maximum and D5 cc of skin were 10.0 ± 3.2 Gy (range 5.5-13.1 Gy) and 6.6 ± 2.2 Gy (range 1.3-9.6 Gy), respectively. Maximal doses immediately adjacent critical organs were as follows: spinal cord < 3.5 Gy, larynx < 6.7 Gy, humeral head < 6.3 Gy, femoral head < 6.5 Gy, small bowel < 6.9 Gy. Planning time was typically an hour. Mean beam-on time was 3.31 ± 0.16 min (range 3.11-3.54 min) and mean treatment time, including patient set up and conebeam CT imaging to beam-off, was 11.35 ± 0.21 min (range 11.11-11.56 min). Average 3-dimentional vector couch correction was (from the skin-marker) 0.49 ± 0.22 cm (range 0.18-0.88 cm).The 3D MLC-based forward planned GRID therapy enhanced target dose for bulky masses including deep-seated large tumors while protecting skin and adjacent critical organs. This same day MLC-GRID treatment provides safe, effective, and convenient treatment by eliminating the risk to therapists and patient of heavy gantry-mounted physical GRID-block. This rapid 3D MLC-GRID planning and treatment can be easily adopted by any radiation clinics on the same day eliminating the need of longer plan optimization and patient-specific quality assurance. MLC-GRID provides all the dosimetry information in the planning system and potentially allow escalating dose to the bulky masses. It may allow for debulking of unresectable large tumors-opening an avenue for a neoadjuvant treatment option. Clinical follow up of these patients is ongoing.

Local Control in Tumor-Targeted Dose Escalation for Localized Prostate Cancer

Tumor-targeted dose escalation may improve biochemical disease-free survival in patients with localized prostate cancer. We report outcomes of dose escalation using a strategy of simultaneous integrated boost or HDR brachytherapy boost.Eighty patients with localized prostate cancer with gross tumor volume (GTV) identified on multiparametric magnetic resonance imaging (mpMRI) were enrolled in this phase 2 non-randomized trial (2012-2016). Patients with GTV > 5mm and less than 33% of total prostate volume were eligible. All patients received whole gland prostate volumetric arc therapy (VMAT), 76 Gy in 38 fractions. GTV dose escalation was delivered by integrated boost VMAT (IB-VMAT) of 95 Gy in 38 fractions (n = 40); or MR-guided HDR boost of 10 Gy in 1 fraction (n = 40). Choice of dose escalation strategy was by physician and/or patient choice. The primary end-point was 3-year local control rates determined by MR-guided biopsy and/or MRI alone. Toxicity data was collected using CTCAE v.4.0. Risk group categorization was similar between the arms; 5% low-, 75% intermediate-, and 20% high-risk. Three patients received 6-months ADT.Median (IQR) follow-up was 55.2 months (48.1-71.4). The overall 5-year biochemical failure-free survival was 92% (95% CI, 85-99), with 5 patients developing biochemical relapse (BCR); 1 IB-VMAT, 4 HDR boost. Local control data was available for 66 patients who agreed to the 3-year post-treatment biopsy (20) or MRI alone (46); 32 in IB-VMAT and 34 in HDR boost. Local control in the boost volume was achieved in 61 patients. One patient in the IB-VMAT arm had persistent disease on biopsy, and subsequently developed late BCR. Intraprostatic relapse outside the GTV was seen in 4 patients at last follow-up; 1 treated with IB-VMAT and 3 with HDR boost. All 4 patients developed BCR. Late G2 genitourinary (GU) toxicity was 22.5% and 27.5% in IB-VMAT and HDR boost, respectively. Late G2 gastrointestinal (GI) toxicity was 5% in each arm. Two G3 (1 GI, 1 GU) toxicities were seen in IB-VMAT.Dose escalation to mpMRI-defined GTV provided high rates of local and biochemical control with limited severe late toxicity. Intraprostatic failures outside the boost volume appeared to correlate with BCR, which suggests that dose escalation to other subclinical intraprostatic regions may be required. Further characterization using molecular classification, beyond usual clinical parameters, may be warranted in order to improve local control.

VMAT Grid Therapy: A Widely Applicable Planning Approach

PurposeTo describe a novel and practical volumetric modulated arc therapy (VMAT) planning approach for grid therapy. Methods and MaterialsDose is prescribed to 1.5-cm diameter spherical contours placed throughout the gross tumor volume (GTV). Placement of spheres is variable, but they must maintain at least a 3-cm (center to center) separation, and the edge of any sphere must be at least 1 cm from any organ at risk (OAR). Three concentric ring structures are used during optimization to confine the highest doses to the center of the spheres and maximize dose sparing between them. The end result is alternating regions of high and low dose throughout the GTV and minimal dose to OARs. High-intensity flattening filter-free (FFF) modes are used to efficiently deliver the plans, and entire treatments typically take only 15 to 20 minutes. ResultsThe approach is illustrated with 2 examples treated at our institution. Patient #1 had a 1703-cm3 mediastinal mass and was prescribed 20 Gray (Gy) to 24 spherical regions within the GTV. Patient #2 had a 3680-cm3 abdominal tumor and was prescribed 18 Gy to 32 spherical regions within the GTV. Both patients received additional consolidative radiation approximately 1 week after the initial VMAT grid treatment. Each patient experienced marked reduction in tumor size and symptomatic relief without treatment-related complications. ConclusionsWe have described in detail a planning approach for VMAT grid therapy treatments that can typically be delivered in a clinically practical time span. The VMAT approach is especially useful for tumors that are surrounded by sensitive critical structures. As many centers offer VMAT treatments, the approach is widely accessible and can be readily implemented once appropriate patient selection and delivery processes are established.

Proton Beam Therapy For Large Hepatocellular Carcinomas In Western Patients

High rates of local control with low risk of hepatotoxicity have been reported in Eastern patients with large hepatocellular carcinomas (HCCs) treated with proton beam therapy (PBT). How generalizable these data are to Western patients is unclear. We present a retrospective study on the clinical outcomes of Western patients with large HCCs treated with PBT at a single institution. Forty-four HCC patients with tumors ≥ 5 cm and ineligible for other liver-directed therapies were treated with PBT between 2014-2019 with a 15-fraction regimen of 45.0-67.5 Gy (RBE). Radiation-induced liver disease (RILD) was defined by a Child-Pugh (CP) score increase of 2 or greater and/or RTOG grade 3 enzyme elevation. Overall survival (OS), progression-free survival (PFS), and local control (LC) were calculated using the Kaplan-Meier method and univariate predictors of OS by Cox regression analysis. Patients represented a high-risk cohort: 50% with BCLC stage C, 27% with CP-B/C cirrhosis, 34% with gross vascular invasion, and a median gross tumor volume (GTV) size and volume of 11.1 cm (5.6-21.5 cm) and 364 cc (48-2439 cc), respectively. The target lesion(s) received prior liver-directed therapies in 39% of patients. Pencil beam scanning was used in the majority of patients (64%), and a simultaneous integrated boost/protection technique was employed in 75% to deliver moderate tumor dose escalation to an average GTV mean BED of 87.0 Gy(RBE) (see table for average dosimetric parameters). Median follow-up for all patients and survivors was 8.5 months and 11 months, respectively. 1-year OS and PFS were 53% (95% CI 33-66%) and 19% (95% CI 10-35%), respectively. Median OS and PFS were 12 months (95% CI 7-25) and 4 months (95% CI 2-9), respectively. 1-yr LC was 93% (95% CI 74-98%), and crude local failure (LF) rate was 14% (n = 6) with one isolated LF. Median time to local failure was 43 months (95% CI 14-not reached). Tumor size and GTV dose were not statistically different between patients with LC and LF. Out of field liver recurrences were the dominant pattern of failure occurring in 61% of patients with disease progression. On univariate analysis, only tumor size was prognostic for OS (HR 1.27, p<0.001). Two (4.5%) grade 3 non-GI toxicities occurred: 1 chest wall pain syndrome/rib fracture and 1 pneumonitis. One acute GI grade ≥2 toxicity (nausea) occurred. Six patients (14%) experienced RILD; all but one patient had baseline CP-B liver function. In this largest series to date of Western HCC patients with high-risk large tumors, moderate dose escalated PBT results in excellent local control rates and acceptable toxicities. Out of field and distant failures remain problematic, which warrant improved systemic therapies in these patients.Abstract 3408; TableParameter Gy (RBE)GTV MeanGTV DmaxGTV D95GTV DminGTV % > 90Gy BEDLiver-GTV MeanAverage61.664.85448.252%15.5Range45.8-69.947.6-71.537.5-69.417.9-68.62.93-21.0 Open table in a new tab

A novel, yet simple MLC-based 3D-crossfire technique for spatially fractionated GRID therapy treatment of deep-seated bulky tumors.

PurposeTreating deep‐seated bulky tumors with traditional single‐field Cerrobend GRID‐blocks has many limitations such as suboptimal target coverage and excessive skin toxicity. Heavy traditional GRID‐blocks are a concern for patient safety at various gantry‐angles and dosimetric detail is not always available without a GRID template in user’s treatment planning system. Herein, we propose a simple, yet clinically useful multileaf collimator (MLC)‐based three‐dimensional (3D)‐crossfire technique to provide sufficient target coverage, reduce skin dose, and potentially escalate tumor dose to deep‐seated bulky tumors.Materials/methodsThirteen patients (multiple sites) who underwent conventional single‐field cerrobend GRID‐block therapy (maximum, 15 Gy in 1 fraction) were re‐planned using an MLC‐based 3D‐crossfire method. Gross tumor volume (GTV) was used to generate a lattice pattern of 10 mm diameter and 20 mm center‐to‐center mimicking conventional GRID‐block using an in‐house MATLAB program. For the same prescription, MLC‐based 3D‐crossfire grid plans were generated using 6‐gantry positions (clockwise) at 60° spacing (210°, 270°, 330°, 30°, 90°, 150°, therefore, each gantry angle associated with a complement angle at 180° apart) with differentially‐weighted 6 or 18 MV beams in Eclipse. For each gantry, standard Millenium120 (Varian) 5 mm MLC leaves were fit to the grid‐pattern with 90° collimator rotation, so that the tunneling dose distribution was achieved. Acuros‐based dose was calculated for heterogeneity corrections. Dosimetric parameters evaluated include: mean GTV dose, GTV dose heterogeneities (peak‐to‐valley dose ratio, PVDR), skin dose and dose to other adjacent critical structures. Additionally, planning time and delivery efficiency was recorded. With 3D‐MLC, dose escalation up to 23 Gy was simulated for all patient's plans.ResultsAll 3D‐MLC crossfire GRID plans exhibited excellent target coverage with mean GTV dose of 13.4 ± 0.5 Gy (range: 12.43–14.24 Gy) and mean PVDR of 2.0 ± 0.3 (range: 1.7–2.4). Maximal and dose to 5 cc of skin were 9.7 ± 2.7 Gy (range: 5.4–14.0 Gy) and 6.3 ± 1.8 Gy (range: 4.1–11.1 Gy), on average respectively. Three‐dimensional‐MLC treatment planning time was about an hour or less. Compared to traditional GRID‐block, average beam on time was 20% less, while providing similar overall treatment time. With 3D‐MLC plans, tumor dose can be escalated up to 23 Gy while respecting skin dose tolerances.ConclusionThe simple MLC‐based 3D‐crossfire GRID‐therapy technique resulted in enhanced target coverage for de‐bulking deep‐seated bulky tumors, reduced skin toxicity and spare adjacent critical structures. This simple MLC‐based approach can be easily adopted by any radiotherapy center. It provides detailed dosimetry and a safe and effective treatment by eliminating the heavy physical GRID‐block and could potentially provide same day treatment. Prospective clinical trial with higher tumor‐dose to bulky deep‐seated tumors is anticipated.

Clinical outcomes after intensity-modulated proton therapy with concurrent chemotherapy for inoperable non-small cell lung cancer

Background & purposeWe report disease control, survival, and toxicity in patients with advanced inoperable non-small cell lung cancer (NSCLC) receiving concurrent chemotherapy and intensity-modulated proton therapy (IMPT) at a single institution. Material and methodsAll patients were treated with IMPT with concurrent chemotherapy. Endpoints assessed were local, regional, and distant control, disease-free survival (DFS), and overall survival (OS). ResultsFifty-one patients were enrolled with a median follow-up time of 23.0 months; 39 (76%) were treated with a simultaneous integrated boost to the gross tumor volume (GTV). The median GTV dose was 67.3 CGE and the median CTV dose was 60.0 CGE. Median OS and DFS times were 33.9 months and 12.6 months. The 3-year local control rate was 78.3%. Treatment was well tolerated, with a grade 3 toxicity rate of 18% (9 events: 4 esophagitis, 3 dermatitis, 1 esophageal stricture, and 1 fatigue) and no grade 4 or 5 toxicity. The most common grade 2 toxic effects were esophagitis (22 [43%]), dermatitis (16 [31%]), pain (15 [29%]), and fatigue (14 [27%]). ConclusionsTreatment of inoperable NSCLC with IMPT and concurrent chemotherapy achieves excellent disease control with tolerable toxicity.

Predictors of Nodal and Metastatic Failure in Early Stage Non–small-cell Lung Cancer After Stereotactic Body Radiation Therapy

Introduction/BackgroundMany patients with early stage non–small-cell lung cancer (ES-NSCLC) undergoing stereotactic body radiation therapy (SBRT) develop metastases, which is associated with poor outcomes. We sought to identify factors predictive of metastases after lung SBRT and created a risk stratification tool. Materials and MethodsWe included 363 patients with ES-NSCLC who received SBRT; the median follow-up was 5.8 years. The following patient and tumor factors were retrospectively analyzed for their association with metastases (defined as nodal and/or distant failure): gender; age; lobe involved; centrality; previous NSCLC; smoking status; gross tumor volume (GTV); T-stage; histology; dose; minimum, maximum, and mean GTV dose; and parenchymal lung failure. A metastasis risk-score linear-model using beta coefficients from a multivariate Cox model was built. ResultsA total of 111 (27.3%) of 406 lesions metastasized. GTV and dose were significantly associated with metastases on univariate and multivariate Cox proportional hazards modeling (P < .001 and hazard ratio [HR], 1.02 per mL; P < .05 and HR, 0.99 per Gy, respectively). Histology, T-stage, centrality, lung parenchymal failures, and previous NSCLC were not associated with development of metastasis. A metastasis risk-score model using GTV and prescription dose was built: risk score = (0.01611 × GTV) − (0.00525 × dose [BED10]). Two risk-score cutoffs separating the cohort into low-, medium-, and high-risk subgroups were examined. The risk score identified significant differences in time to metastases between low-, medium-, and high-risk patients (P < .001), with 3-year estimates of 81.1%, 63.8%, and 38%, respectively. ConclusionGTV and radiation dose are associated with time to metastasis and may be used to identify patients at higher risk of metastasis after lung SBRT.

Predictors of Nodal And Metastatic Failure in Early Stage Non-Small Cell Lung Cancer after Stereotactic Body Radiation Therapy

Up to 30% of early stage non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiation therapy (SBRT) develop metastatic disease. While lung parenchymal failures after lung SBRT are thought to be salvageable if detected early, development of nodal and distant metastases are challenging situations that can seriously compromise patient outcomes. We sought to identify factors predictive of metastasis after lung SBRT. Overall, 363 patients with early-stage NSCLC (T1a, T1b and T2a N0 M0 as per AJCC 7th edition) that received SBRT in 3-5 fractions were included in this retrospective analysis. Multiple patient and tumor factors were analyzed for their association with time to a combined nodal and/or distant metastatic failure: sex; age; lobe involved; previous history of NSCLC; gross tumor volume (GTV); T stage; histology (adenocarcinoma, squamous cell carcinoma, NSCLC not otherwise specified, or no pathology); radiation dose (biologically equivalent dose using alpha/beta=10 [BED10]); prescription dose; minimum, maximum, and mean dose to GTV; and parenchymal lung sites of failure (in-field, same lobe but not in-field, different ispilateral lobe, and contralateral lung). A metastasis risk score linear model using beta coefficients from a multivariate Cox model as weighting factors was built for variables significant on multivariate analysis. GTV and radiation dose were significant on univariate analysis. A previous history of NSCLC (p=0.84), histology (p=0.45), T stage (p=0.49), and subsequent lung parenchymal failures (p>0.11) did not increase the risk of metastasis. On multivariate Cox proportional hazards modeling, GTV and radiation dose remained significantly associated with time to metastasis (p<0.001 and p=0.044, respectively). A metastasis risk score model using GTV and radiation dose was built: [Risk score = (0.01611 x GTV) – (0.00525 x prescription dose (BED10))]. Two risk score cutoffs separating the cohort into low risk and high risk were examined. Using a cutoff identifying patients with the highest risk scores in the cohort, a significant difference in time to metastases was identified between 325 low risk and 38 high risk patients (p<0.001) with 2-year metastases-free estimates of 82.5% (95% CI 77.5-87.8%) and 48.8% (95% CI 32.8-72.7%). Using a less stringent cutoff separating our cohort into 248 low risk patients and 115 high risk patients revealed similar results (p=0.0087) with 2-year estimates of metastases-free survival of 85.4% (95% CI 80.1-91.1%) and 65.4% (95% CI 55.5-76.9%). Based on the model, a 25cc tumor would require 153 Gy BED10 to keep the 2-year metastases-free survival at 85%. GTV and radiation dose are associated with time to metastasis. A risk score can be used to identify patients at high risk for metastasis after SBRT for early stage NSCLC.

Comparison of Acurosand Anisotropic Analytical Algorithm for dose calculation in the treatment of Early-Stage Non-Small Cell Lung Cancer Utilizing Stereotactic Body Radiation Therapy

Stereotactic Body Radiation Therapy (SBRT) is an established technique used to treat early-stage Non-Small Cell Lung Cancer (NSCLC). Currently, photon treatment plans are calculated using convolution-superposition algorithms (CSAs) such as the Anisotropic Analytical Algorithm (AAA). The latest generation of algorithms look to solve the Linear Boltzmann Transport Equation (LBTE) in one of two ways: analytically or indirectly through statistics (Monte Carlo). CSAs are more commonly used but suffer from inaccuracies in heterogeneous media. Acuros External Beam (AXB) directly accounts for heterogeneities by solving the LBTE, providing a more accurate dose calculation than AAA. We evaluated tissue dose differences between the AAA and AXB generated plans. We identified 15 cases of Stage I-II NSCLC treated with curative intent SBRT at our institution from 2015-2016 who were planned in AAA to receive 50 Gy in 5 fractions using a treatment planning system. The patients’ delivered plans were retrospectively recalculated using AXB. The dose volume histogram was generated for structures commonly contoured in lung SBRT based on RTOG 0813; structures included gross tumor volume (GTV) and planning target volume (PTV) and the organs at risk (OARS), specifically the spinal cord, skin, heart, great vessels, chest wall, brachial plexus, total lung, and bronchi. Both peripheral and central tumors were included. Dose to 95% of the PTV volume was the primary endpoint. The Wilcoxon signed-rank test tested variance between the dose distribution generated by AXB and by AAA. PTV 95% dose differed significantly between AAA and AXB generated plans (p=0.0027).The mean, min, and max PTV 95% dose generated by AAA were 4966 cGy (SD=77.260 cGy), 4722 cGy, and 5002 cGy, respectively, whereas, the AXB generated plan yielded values of 4890 cGy (STD=118.4 cGy), 4589 cGy, and 5065 cGy, respectively. The mean GTV dose generated by AAA was higher overall (mean=5619 cGy) when compared to GTV dose calculated by AXB (mean = 5360 cGy); however, this difference was not significant in our cohort. On average, the PTV 95% dose was 70.60 cGy (SD =91.68) higher for AAA plans compared to plans re-calculated with AXB. The D0.03 cc for the esophagus, spinal cord, skin, heart, great vessels, and bronchi were on average 13.57 cGy (p=0.017), 7.293 cGy (p=0.0004), 5.488 cGy [NS], and 10.854 cGy [NS] lower when re-calculated with AXB, respectively. The D0.03 cc for the chest wall and brachial plexus were on average 46.51 cGy (p=0.04) and 8.043 cGy [NS] higher when re-calculated with AXB. We found a statistically difference in dose distribution for the PTV 95% dose for AAA plans re-calculated with AXB. Overall, AXB re-calculation of the PTV 95% dose resulted in a lower dose distribution to the target when compared to the original plan, which was calculated in AAA. Given that AXB has shown to more accurately calculate dose-distribution. Our data suggests that AAA model overestimates the PTV 95% dose in lung SBRT.

Histology, Tumor Volume, and Radiation Dose Predict Outcomes in NSCLC Patients After Stereotactic Ablative Radiotherapy.

It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed. At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR]= 1.01 per mL, p= 0.0044) and histology (p= 0.0225) were independently associated with involved lobe failure. GTV (HR= 1.013, p= 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/β= 10 [BED10], HR= 2.380, p= 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy× 4 or 10 Gy× 5 versus 18 Gy or 20 Gy× 3: HR= 3.530, p= 0.0447, confirmed by propensity score matching) and was independent of GTV (HR= 1.014 per mL, 95% confidence interval: 1.005-1.022, p= 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p= 0.12 and p= 0.31, respectively). In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy× 4 or 10 G× 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.

Clinical Results of Mean GTV Dose Optimized Robotic-Guided Stereotactic Body Radiation Therapy for Lung Tumors.

We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean dose optimized stereotactic body radiation therapy (SBRT) for primary and secondary lung tumors with and without robotic real-time motion compensation. Between 2011 and 2017, 208 patients were treated with SBRT for 111 primary lung tumors and 163 lung metastases with a median GTV of 8.2 cc (0.3-174.0 cc). Monte Carlo dose optimization was performed prioritizing GTV mean dose at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The median GTV mean biological effective dose (BED)10 was 162.0 Gy10 (34.2-253.6 Gy10) and the prescribed PTV BED10 ranged 23.6-151.2 Gy10 (median, 100.8 Gy10). Motion compensation was realized through direct tracking (44.9%), fiducial tracking (4.4%), and internal target volume (ITV) concepts with small (≤5 mm, 33.2%) or large (>5 mm, 17.5%) motion. The local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity were analyzed. Median follow-up was 14.5 months (1-72 months). The 2-year actuarial LC, PFS, and OS rates were 93.1, 43.2, and 62.4%, and the median PFS and OS were 18.0 and 39.8 months, respectively. In univariate analysis, prior local irradiation (hazard ratio (HR) 0.18, confidence interval (CI) 0.05-0.63, p = 0.01), GTV/PTV (HR 1.01-1.02, CI 1.01-1.04, p < 0.02), and PTV prescription, mean GTV, and maximum plan BED10 (HR 0.97-0.99, CI 0.96-0.99, p < 0.01) were predictive for LC while the tracking method was not (p = 0.97). For PFS and OS, multivariate analysis showed Karnofsky Index (p < 0.01) and tumor stage (p ≤ 0.02) to be significant factors for outcome prediction. Late radiation pneumonitis or chronic rip fractures grade 1-2 were observed in 5.3% of the patients. Grade ≥3 side effects did not occur. Robotic SBRT is a safe and effective treatment for lung tumors. Reducing the PTV prescription and keeping high GTV mean doses allowed the reduction of toxicity while maintaining high local tumor control. The use of real-time motion compensation is strongly advised, however, well-performed ITV motion compensation may be used alternatively when direct tracking is not feasible.

Influence of MRI-CT fusion image on gross tumor volume delineation and dose distribution for radiation of primary tumors of cervical vertebra

Objective To compare the differences of gross tumor volume (GTV) and dose distribution between MRI-CT fusion imaging and CT-based imaging and investigate the dose difference in the therapeutic regime. Methods Ten patients diagnosed with primary tumors of the cervical vertebra between 2013 and 2014 were enrolled. Prior to radiotherapy, the imaging data of MRI examination (GE Discovery MR 750 3.0T) were collected, transfered into the Eclipse system and subject to fusion with CT images. GTV delineation, organ at risk (OAR) delineation and dose distribution discrepancy induced by target volume differences were analyzed and statistically compared between the MRI-CT fusion and CT-based images. GTV delineation and dose parameters among different radiologists between two approches were analyzed by analysis of variance (ANOVA) and paired t-test. Non-normally distributed variables were analyzed by Wilcoxon rank-sum test. The reliability of intraclass correlation coefficient (ICC) was assessed. Results The GTVMRI-CT volume was larger compared with the GTVCT volume. The volume overlap index was 0.84±0.17.The cordMRI-CT volume was significantly less than the cordCT volume (P=0.001). For 5 radiologists, the ICCMRI-CT was larger than ICCCT. The DmaxMRI-CT of the spinal cord was (46.00±1.09) Gy, significantly less than (52.39±1.34) Gy for the DmaxCT(P=0.014). Conclusions It is unlikely to miss the target delineation on MRI-CT fusion imaging. MRI-CT fusion imaging can minimize the discrepancy of interobserver radiologists and cause dosimetric advantages. Key words: Tomotherapy, X-ray computed; Magnetic resonance imaging; Gross tumor volume; Cervical neoplasm/intensity-modulated radiotherapy

Single fraction computed tomography-guided high-dose-rate brachytherapy or stereotactic body radiotherapy for primary and metastatic lung tumors?

PurposeTo provide a pilot dosimetric study of computed tomography (CT)-guided high-dose-rate (HDR) brachytherapy (BRT) and stereotactic body radiotherapy (SBRT) for primary and metastatic lung lesions.Material and methodsFor nine lung primary and metastasis patients, 3D image-based BRT plan using a single virtual catheter was planned for 34 Gy in single fraction to the gross tumor volume (GTV) + 3 mm margin to account for tumor deformation. These plans were compared to margin-based (MB-) and robustness optimized (RO-) SBRT, assuming the same tumor deformation under real-time tumor tracking. Consistent dose calculation was ensured for both BRT and SBRT plans using the same class of collapsed cone convolution superposition algorithm. Plan quality metrics were compared by Friedman tests and Wilcoxon t-tests.Results and ConclusionsBrachytherapy plans showed significant higher GTV mean dose compared to MB- and RO-SBRT (122.2 Gy vs. 50.4 and 44.7 Gy, p < 0.05), and better dose gradient index (R50) = 2.9 vs. 4.3 and 8.4 for MB- and RO-SBRT, respectively. Dose constraints per the RTOG 0915 protocol were achieved for all critical organs except chest wall in BRT. All other dose-volume histograms (DVH) metrics are comparable between BRT and SBRT. Treatment delivery time of BRT and SBRT plans significantly increased and decreased with increasing GTV size, respectively. SBRT using advanced MLC tracking technique and non-coplanar VMAT can achieve comparable dosimetric quality to HDR BRT. Whether or not, the significantly higher GTV dose can increase killing of radioresistant tumor cells and offset the effect of tumor reoxygenation in single fraction BRT, requires further clinical investigation.

Stereotactic Radiosurgery with Mouse Phantom Quality Assurance Using the Sarrp in a Murine Melanoma Brain Metastases Model

To establish a novel preclinical model for stereotactic radiosurgery with combined mouse phantom quality assurance in the setting of murine melanoma brain metastases. All protocols were approved by our institutional IACUC. C57B6 mice underwent intracranial stereotactic injection of B16-F10 melanoma cells. 300 cells per 1 microliter suspension in PBS was injected 2 mm lateral and 1.5 mm anterior to the bregma. The needle was inserted to a depth of 2.5 mm from the surface of the brain. T1-post contrast MRI with gadolinium was performed on day 11 post injection using a 9.4 Tesla MRI (Bruker). DICOM images for MRI based planning were fused with cone beam computed tomography (CBCT) simulation performed on the same mice using the SARRP (Xstrahl). Anatomical match was completed for the MRI to CBCT fusion and gross tumor volume (GTV) was contoured. A single sagittal arc using a 3 mm collimator was used to plan a 60 degree arc encompassing the GTV. 18 Gy was prescribed to a point dose. Radiation was delivered on the same day and repeat MRI was performed 7 days after radiation treatment on day 18. Radiation dose delivered to the mouse was confirmed using two mouse phantoms previously published by Welch et al. One mouse phantom is in the axial orientation and one phantom is in the sagittal orientation. A representative planning MRI scan from Day 10 was fused to the CBCT obtained from the two mouse phantoms and radiochromic film was placed in the region of the presumed GTV. Optical density of the film was analyzed using film analysis based on our institutional ion chamber measurement and H-D curve. MRI images were analyzed with 3D slicer for tumor volumes. Statistics used include T-test for volume comparison and Kaplan Meier curve for survival. The experiment was designed with two arms. Mouse injected with melanoma cells without radiation treatment (no SRS) and mouse injected with melanoma cells treated with stereotactic radiosurgery of 18 Gy in 1 fraction (SRS). The average tumor volume at Day 11 was 2.48±1.37 mm3 in the no SRS arm versus 3.75±1.19 mm3 in the SRS arm (NS). In the SRS arm, GTV Dose max (Dmax), mean dose, and D95 was 2048±207 cGy, 1785±14 cGy, and 1722±12 cGy respectively. Using the axial and saggital phantom mice, the radiochromic film showed close precision as compared to projected isodose lines. Radiochromic film analysis showed a Dmax of 1903.4 cGy and 1972.7 cGy in the axial and saggital phantom mice respectively. Tumor volume 7 days after SRS showed 7.34±8.24 mm3 in the SRS arm and 60.20±40.4 mm3in the no SRS arm (p=0.009). All mice with no SRS died. Median overall survival (mOS) of no SRS group was 19 days. mOS was not reached in the SRS group with one death noted. Single fraction SRS of 18 Gy using a single arc can be delivered accurately with MRI T1-post contrast based treatment planning. Phantom mice allows for verification of dose delivery and accuracy.

Breathing-motion-compensated robotic guided stereotactic body radiation therapy : Patterns of failure analysis.

We retrospectively evaluated the patterns of failure for robotic guided real-time breathing-motion-compensated (BMC) stereotactic body radiation therapy (SBRT) in the treatment of tumors in moving organs. Between 2011 and 2016, atotal of 198 patients with 280 lung, liver, and abdominal tumors were treated with BMC-SBRT. The median gross tumor volume (GTV) was 12.3 cc (0.1-372.0 cc). Medians of mean GTV BEDα/β=10 Gy (BED= biological effective dose) was 148.5 Gy10 (31.5-233.3 Gy10) and prescribed planning target volume (PTV) BEDα/β=10 Gy was 89.7 Gy10 (28.8-151.2 Gy10), respectively. We analyzed overall survival (OS) and local control (LC) based on various factors, including BEDs with α/β ratios of 15 Gy (lung metastases), 21 Gy (primary lung tumors), and 27 Gy (liver metastases). Median follow-up was 10.4months (2.0-59.0 months). The 2‑year actuarial LC was 100 and 86.4% for primary early and advanced stage lung tumors, respectively, 100% for lung metastases, 82.2% for liver metastases, and 90% for extrapulmonary extrahepatic metastases. The 2‑year OS rate was 47.9% for all patients. In uni- and multivariate analysis, comparatively lower PTV prescription dose (equivalence of 3× 12-13 Gy) and higher average GTV dose (equivalence of 3× 18 Gy) to current practice were significantly associated with LC. For OS, Karnofsky performance score (100%), gender (female), and SBRT without simultaneous chemotherapy were significant prognostic factors. Grade3 side effects were rare (0.5%). Robotic guided BMC-SBRT can be considered asafe and effective treatment for solid tumors in moving organs. To reach sufficient local control rates, high average GTV doses are necessary. Further prospective studies are warranted to evaluate these points.

Target volume dose and clinical outcome in radiotherapy for primary marginal zone lymphoma of the ocular adnexa.

The aim of the present study was to determine the optimal dose and optimal target volume for marginal zone lymphoma of the ocular adnexa. Between January, 2008 and December, 2013, 40 patients with histologically proven primary marginal zone lymphoma of the ocular adnexa who underwent radiotherapy at the Tokyo Medical University were evaluated. The prescribed dose was 30 Gy in 15 fractions to the iso-center. Doses to the gross tumor volume (GTV), conjunctiva, bulbus oculi, retina and retrobulbar space were investigated, and the association between dose-volume factors and clinical outcome was analyzed. The overall and local progression-free survival rates at 3 and 5 years were 100% during a median observation period of 32 months. Two patients relapsed in the contralateral ocular adnexa. The progression-free survival rates at 3 and 5 years were 100 and 93.3%, respectively. The mean dose was 2.0 and 1.9 Gy for targets receiving 95% of the GTV dose (D95). The minimum dose was 0.9–2.0 Gy (median, 1.8 Gy). Thus, primary marginal zone lymphoma of the ocular adnexa favorably responded to lower doses of radiation, compared with prescribed doses to the iso-center. A radiation dose of 27 Gy in 15 fractions at D95 of GTV appeared to be optimal.

Early Assessment of Treatment Responses During Radiation Therapy for Lung Cancer Using Quantitative Analysis of Daily Computed Tomography

To investigate early tumor and normal tissue responses during the course of radiation therapy (RT) for lung cancer using quantitative analysis of daily computed tomography (CT) scans. Daily diagnostic-quality CT scans acquired using CT-on-rails during CT-guided RT for 20 lung cancer patients were quantitatively analyzed. On each daily CT set, the contours of the gross tumor volume (GTV) and lungs were generated and the radiation dose delivered was reconstructed. The changes in CT image intensity (Hounsfield unit [HU]) features in the GTV and the multiple normal lung tissue shells around the GTV were extracted from the daily CT scans. The associations between the changes in the mean HUs, GTV, accumulated dose during RT delivery, and patient survival rate were analyzed. During the RT course, radiation can induce substantial changes in the HU histogram features on the daily CT scans, with reductions in the GTV mean HUs (dH) observed in the range of 11 to 48 HU (median 30). The dH is statistically related to the accumulated GTV dose (R2>0.99) and correlates weakly with the change in GTV (R2=0.3481). Statistically significant increases in patient survival rates (P=.038) were observed for patients with a higher dH in the GTV. In the normal lung, the 4 regions proximal to the GTV showed statistically significant (P<.001) HU reductions from the first to last fraction. Quantitative analysis of the daily CT scans indicated that the mean HUs in lung tumor and surrounding normal tissue were reduced during RT delivery. This reduction was observed in the early phase of the treatment, is patient specific, and correlated with the delivered dose. A larger HU reduction in the GTV correlated significantly with greater patient survival. The changes in daily CT features, such as the mean HU, can be used for early assessment of the radiation response during RT delivery for lung cancer.

Dosimetric Study of Automatic Brain Metastases Planning in Comparison with Conventional Multi-Isocenter Dynamic Conformal Arc Therapy and Gamma Knife Radiosurgery for Multiple Brain Metastases.

ObjectiveThe efficacy of stereotactic radiosurgery (SRS) using Gamma Knife (GK) (Elekta, Tokyo) is well known. Recently, Automatic Brain Metastases Planning (ABMP) Element (BrainLAB, Tokyo) for a LINAC-based radiation system was commercially released. It covers multiple off-isocenter targets simultaneously inside a multi-leaf collimator field and enables SRS / stereotactic radiotherapy (SRT) with a single group of LINAC-based dynamic conformal multi-arcs (DCA) for multiple brain metastases. In this study, dose planning of ABMP (ABMP-single isocenter DCA (ABMP-SIDCA)) for SRS of small multiple brain metastases was evaluated in comparison with those of conventional multi-isocenter DCA (MIDCA-SRS) (iPlan, BrainLAB, Tokyo) and GK-SRS (GKRS).MethodsSimulation planning was performed with ABMP-SIDCA and GKRS in the two cases of multiple small brain metastases (nine tumors in both), which had been originally treated with iPlan-MIDCA. First, a dosimetric comparison was done between ABMP-SIDCA and iPlan-MIDCA in the same setting of planning target volume (PTV) margin and D95 (dose covering 95% of PTV volume). Second, dosimetry of GKRS with a margin dose of 20 Gy was compared with that of ABMP-SIDCA in the setting of PTV margin of 0, 1 mm, and 2 mm, and D95=100% dose (20 Gy).ResultsFirst, the maximum dose of PTV and minimum dose of gross tumor volume (GTV) were significantly greater in ABMP-SIDCA than in iPlan-MIDCA. Conformity index (CI, 1/Paddick’s CI) and gradient index (GI, V (half of prescription dose) / V (prescription dose)) in ABMP-SIDCA were comparable with those of iPlan-MIDCA. Second, PIV (prescription isodose volume) of GKRS was consistent with that of 1 mm margin - ABMP-SIDCA plan in Case 1 and that of no-margin ABMP-SIDCA plan in Case 2. Considering the dose gradient, the mean of V (half of prescription dose) of ABMP-SIDCA was not broad, comparable to GKRS, in either Case 1 or 2.ConclusionsThe conformity and dose gradient with ABMP-SIDCA were as good as those of conventional MIDCA for each lesion. If the conditions of the LINAC system permit a minimal PTV margin (1 mm or less), ABMP-SIDCA might provide excellent dose fall-off comparable with that of GKRS thereby enabling a short treatment time.

Gross tumor volume dosimetry and prognosis of esophageal carcinoma treated with three-dimensional radiotherapy: a study of 548 patients

Objective To investigate the effects of dosimetric differences in gross tumor volume (GTV) on local control and survival rates in patients with esophageal carcinoma undergoing three-dimensional (3D) radiotherapy, and to provide a basis for clinical treatment. Methods From January 2004 to December 2010, 548 patients with esophageal carcinoma received conventional fractionated 3D radiotherapy with a prescribed dose of 60 Gy. All patients were divided into low-dose group and high-dose group according to the dosimetric differences in GTV.The survival and local control rates were compared between the two groups. The survival rates were calculated using the Kaplan-Meier method and analyzed using the logrank test. The Cox regression model was used for the multivariate prognostic analysis. Results The number of sample were 456 and 216 patients at 5 and 7 years followed time. The 1-, 3-, 5-, and 7-year local control rates were significantly higher in the high-dose group than in the low-dose group (83.5% vs. 71.3%, 62.6% vs. 44.8%, 57.5% vs. 41.7%, 52.9% vs. 38.8%, P=0.000). The 1-, 3-, 5-, and 7-year survival rates were also significantly higher in the high-dose group than in the low-dose group (79.6% vs. 66.3%, 44.3% vs. 29.7%, 34.0% vs. 21.8%, 26.1% vs. 17.0%, P=0.000). The univariate prognostic analysis using the Cox regression model showed that Dmin, Dmean, and D100 for GTV were prognostic factors (P=0.000, 0.001, 0.000). In all the 548 patients, 201 were assigned to the high-dose group and the others to the low-dose group. Compared with the high-dose group, the low-dose group showed significantly larger GTV (38.2 vs. 48.1 cm3, P=0.002) and more advanced T stages (P=0.035). The stratified analysis showed that the 1-, 3-, 5-, and 7-year local control and survival rates were significantly higher in the high-dose group than in the low-dose group, regardless of tumor location, GTV, TNM stage, or chemotherapy. The multivariate analysis using the Cox regression model indicated that tumor location and grouping based on the radiation dose to GTV were independent prognostic factors. Conclusions In 3D radiotherapy for treating esophageal carcinoma, a high-quality treatment plan and GTV dose assurance improve the survival rates in patients. The patients with lower Dmin, Dmean, and D100 for GTV than the prescribed dose have a poor prognosis. Key words: Esophageal neoplasms/three-dimensional radiotherapy; Gross tumor volume; Prognosis