Stereotactic image-guided neoadjuvant ablative single-dose radiation, then lumpectomy, for early breast cancer: the SIGNAL prospective single-arm trial of single-dose radiation therapy.

Background and Purpose: Adjuvant whole-breast irradiation after breast-conserving surgery, typically delivered over several weeks, is the traditional standard of care for low-risk breast cancer. More recently, hypofractionated, partial-breast irradiation has increasingly become established. Neoadjuvant single-fraction radiotherapy (rt) is an uncommon approach wherein the unresected lesion is irradiated preoperatively in a single fraction. We developed the signal (Stereotactic Image-Guided Neoadjuvant Ablative Radiation Then Lumpectomy) trial, a prospective single-arm trial to test our hypothesis that, for low-risk carcinoma of the breast, the preoperative single-fraction approach would be feasible and safe. Methods: Patients presenting with early-stage (T < 3 cm), estrogen-positive, clinically node-negative invasive carcinoma of the breast with tumours at least 2 cm away from skin and chest wall were enrolled. All patients received prone breast magnetic resonance imaging (mri) and prone computed tomography simulation. Treatable patients received a single 21 Gy fraction of external-beam rt (as volumetric-modulated arc therapy) to the primary lesion in the breast, followed by definitive surgery 1 week later. The primary endpoints at 3 weeks, 6 months, and 1 year were toxicity and cosmesis (that is, safety) and feasibility (defined as the proportion of mri-appropriate patients receiving rt). Results: Of 52 patients accrued, 27 were successfully treated. The initial dosimetric constraints resulted in a feasibility failure, because only 57% of eligible patients were successfully treated. Revised dosimetric constraints were developed, after which 100% of patients meeting mri criteria were treated according to protocol. At 3 weeks, 6 months, and 1 year after the operation, toxicity, patient- and physician-rated cosmesis, and quality of life were not significantly different from baseline. Conclusions: The signal trial presents a feasible method of implementing single-dose preoperative rt in early-stage breast cancer. This pilot study did not identify any significant toxicity and demonstrated excellent cosmetic and quality-of-life outcomes. Future randomized multi-arm studies are required to corroborate these findings.

Determination and comparison of radiotherapy dose responses for hepatocellular carcinoma and metastatic colorectal liver tumours.

OBJECTIVE: The purpose of this study was to seek radiation dose responses separately for primary hepatocellular carcinoma (HCC) and metastatic (MET) colorectal liver tumours to establish tumour control probabilities (TCPs) for radiotherapy (RT) of liver tumours. METHODS: The records of 36 HCC and 26 MET colorectal liver tumour patients were reviewed. The median dose per fraction and total dose were 4 Gy (2-10 Gy) and 52 Gy (29-83 Gy) for the HCC group and 3.6 Gy (2.0-13.0 Gy) and 55 Gy (30-80 Gy) for the MET group, respectively. Median tumour diameter was 6.6 cm (3.0-18.0 cm) and 5.0 cm (1.0-13.0 cm) for the HCC and MET groups, respectively. A logistic TCP model was fitted to the response data for each group using the maximum likelihood method. RESULTS: 50% and 90% probabilities of 6-month local control were estimated to be achievable by 2 Gy per fraction equivalent doses (α/ß=10 Gy) of 53 Gy and 84 Gy for the HCC group and 70 Gy and 95 Gy for the MET group, respectively. Actuarial 1-year local control for the HCC and MET groups was 65% (45-85%) and 32% (6-58%), respectively, whereas median time to failure was 543 days (374-711 days) and 183 days (72-294 days), respectively. CONCLUSION: Dose-response relationships were found and modelled for the HCC and MET patient groups, with a higher dose required to control MET tumours. RT offers better local control for HCC than for MET colorectal liver tumours at our institution. ADVANCES IN KNOWLEDGE: An improved understanding of radiation dose-response relationships for primary and MET colorectal liver tumours will help inform future dose prescriptions.

Development of a novel ArcCHECK(™) insert for routine quality assurance of VMAT delivery including dose calculation with inhomogeneities.

PURPOSE: To design a versatile, nonhomogeneous insert for the dose verification phantom ArcCHECK(™) (Sun Nuclear Corp., FL) and to demonstrate its usefulness for the verification of dose distributions in inhomogeneous media. As an example, we demonstrate it can be used clinically for routine quality assurance of two volumetric modulated arc therapy (VMAT) systems for lung stereotactic body radiation therapy (SBRT): SmartArc(®) (Pinnacle(3), Philips Radiation Oncology Systems, Fitchburg, WI) and RapidArc(®) (Eclipse(™), Varian Medical Systems, Palo Alto, CA). METHODS: The cylindrical detector array ArcCHECK(™) has a retractable homogeneous acrylic insert. In this work, we designed and manufactured a customized heterogeneous insert with densities that simulate soft tissue, lung, bone, and air. The insert offers several possible heterogeneity configurations and multiple locations for point dose measurements. SmartArc(®) and RapidArc(®) plans for lung SBRT were generated and copied to ArcCHECK(™) for each inhomogeneity configuration. Dose delivery was done on a Varian 2100 ix linac. The evaluation of dose distributions was based on gamma analysis of the diode measurements and point doses measurements at different positions near the inhomogeneities. RESULTS: The insert was successfully manufactured and tested with different measurements of VMAT plans. Dose distributions measured with the homogeneous insert showed gamma passing rates similar to our clinical results (∼99%) for both treatment-planning systems. Using nonhomogeneous inserts decreased the passing rates by up to 3.6% in the examples studied. Overall, SmartArc(®) plans showed better gamma passing rates for nonhomogeneous measurements. The discrepancy between calculated and measured point doses was increased up to 6.5% for the nonhomogeneous insert depending on the inhomogeneity configuration and measurement location. SmartArc(®) and RapidArc(®) plans had similar plan quality but RapidArc(®) plans had significantly higher monitor units (up to 70%). CONCLUSIONS: A versatile, nonhomogeneous insert was developed for ArcCHECK(™) for an easy and quick evaluation of dose calculations with nonhomogeneous media and for comparison of different treatment planning systems. The device was tested for SmartArc(®) and RapidArc(®) plans for lung SBRT, showing the uncertainties of dose calculations with inhomogeneities. The new insert combines the convenience of the ArcCHECK(™) and the possibility of assessing dose distributions in inhomogeneous media.

Poster - Thur Eve - 17: Control point analysis comparison of three different treatment planning and delivery complexity levels using a commercial three dimensional diode array.

PURPOSE: To use Control Point Analysis (Sun Nuclear Corporation, Melbourne, Florida, USA) to analyze and compare delivered VMAT plans for three different treatment planning complexity levels. METHODS: Nineteen patients were chosen and fully anonymized for the purpose of this study. Ten SBRT, six H&N, one breast and two prostate VMAT plans were generated on Pinnacle3 and delivered on a Varian LINAC. The delivered dose was measured using ArcCHECK™. Each plan was analyzed using SNC Patient 6 and Control Point Analysis. Gamma passing percentage was used to assess the differences between the measured and planned dose distributions and to assess the role of various control point binning scenarios. RESULTS: The prostate cases reported the highest gamma passing percentages for SNC Patient 6 (99.3%-99.5%,3%/3mm) and Control Point Analysis (99.1--99.3%,3%/3mm). The mean percentage of passing control point sectors for the prostate cases increased from 48.9±3.1% for individual control points to 69.5 ± 3.9% for 5 control points binned together to 100±0% for 10 control points binned together. Over all, there was a trend in the percentage of sectors passing gamma analysis increasing with the increase of the number of control points binned together in one sector for both passing criteria considered (48.9±3.1% for individual control points to 69.5±3.9% for 5 control points binned together in one sector to 100±0% for 10 control points binned together in one sector for the prostate). CONCLUSION: The delivery accuracy per control point depends on the MU/control point (SBRT) and the plan degree of modulation (H&N).

Sci-Thur PM: YIS - 04: Forcing lateral electron disequilibrium to spare lung tissue: A novel technique for SBRT of small lung tumours.

Stereotactic body radiation therapy(SBRT), a technique that uses tightly conformed Megavoltage(MV) x-ray fields, improves local control of lung cancer. However, small MV x-ray fields can cause lateral electron disequilibrium(LED), which reduces the dose within lung. These effects are difficult to predict and are presently a cause of alarm for the radiotherapy community. Previously, we developed The Relative Depth Dose Factor(RDDF), which is an indicator of the extent of LED (RDDF < 1). We propose a positive application of LED for lung sparing in SBRT: LED can be exploited to irradiate a small tumor while greatly reducing the dose in surrounding lung tissue. The Monte Carlo code, DOSXYZnrc, was employed to calculate dose within a cylindrical lung phantom. The phantom's diameter and height were set to 25 cm, and consisted of water and lung (density = 0.25g/cm3 ) shells surrounding a small water tumor (volume = 0.8 cm3 ). Two 180° 6MV arcs were focused onto the tumor with field sizes of 1×1cm2 (RDDF∼0.5) and 3×3cm2 (RDDF∼1). Analyzing dose results, the 1×1cm2 arc reduced dose within lung and water tissues by 70% and 80% compared to the 3×3cm2 arc. Although, central tumor dose was also reduced by 15% using the 1×1cm2 arc, these reductions can be offset by escalating the prescription dose appropriately. Using the RDDF as a guideline, it's possible to design a SBRT treatment plan that reduces lung dose while maintaining relatively high tumor dose levels. Clinical application requires an accurate dose algorithm and may lower SBRT dose-induced toxicity levels in patients.

Poster - Thur Eve - 53: Analysis of the distribution of dose delivery during respiratory-gated step-and-shoot IMRT for lung cancer radiotherapy.

Respiratory motion is a large source of dosimetric error when treating lung cancer with Intensity Modulated Radiation Therapy (IMRT). The asynchronicity of the tumour motion and the multileaf collimator (MLC) used to modulate the radiation beam intensity, leads to the interplay effect. One method to account for this effect is respiratory gating. Treatment planning optimization for gated IMRT is performed on a subset average 4D-CT which includes the phases surrounding end exhalation. However, this assumes that the beam delivery will be evenly distributed amongst those phases. This study investigates the distribution of beam delivery during gated step-and-shoot IMRT (SS-IMRT) for both early and late stage non-small cell lung cancer (NSCLC). Four Stage I NSCLC patients, prescribed a dose of 54 Gy in 3 fractions, and five Stage III NSCLC patients, prescribed a dose of 60 Gy in 30 fractions, were retrospectively planned with high and low modulation beams-IMRT, and delivered using the QUASAR™ Programmable Respiratory Motion Platform with 15 mm and 20 mm peak-to-peak sinusoidal motion and real patient breathing motion. The percent monitor units delivered at each phase were compared. For Stage I patients, the monitor units delivered were evenly distributed over the gating window due to a high number of monitor units delivered per control point. For Stage III patients, as the complexity of SS-IMRT increases, there were more monitor units delivered in the initial gating phase. This dose discrepancy could potentially lead to geographic miss of the tumour and should be taken into account during treatment planning.

Poster - Thur Eve - 63: Dosimetric impact of breathing motion in lung SBRT: Dual vs single volumetric modulated arc therapy.

Volumetric modulated arc therapy (VMAT) is a time efficient treatment delivery platform capable of producing highly conformal dose distributions with a single 360° arc. However, additional arcs can be used to further improve the conformal dose distribution. For these reasons, VMAT is often used for stereotactic body radiation therapy (SBRT) in which the treatment deliveries are hypofractionated. The dosimetric impact of tumour motion, especially in lung SBRT where tumour motion is most significant and treatments are hypofractionated, has always been a clinical concern. Through the use of 4-dimensional computed tomography (4D-CT), 4D dose distributions can be calculated that account for dosimetric errors due to motion and temporal variation in lung density that are not accounted for in clinical treatment plans. The purpose of this study was to quantify the dosimetric differences that arise due to tumour motion and variations in lung density between single and dual VMAT SBRT treatment plans. Six patients previously treated for stage I/II non-small-cell lung cancer with SBRT were included in this retrospective study. 3D and 4D dose distributions were calculated for both single and dual arc plans for each of the six patients. Dose-volume histogram metrics are reported for the target and critical structures. The results show significant differences (p ≤ 0.05) between the 3D and 4D dose distributions for the ratio of the prescription isodose volume to the primary target volume (PTV). This result was consistent for both single and dual arc VMAT plans.

Poster - Thur Eve - 33: A comprehensive analysis of the effect of respiratory motion on the delivery of IMRT to advanced stage non-small cell lung cancer.

The goal of this work was to quantify the interplay effect of various IMRT delivery techniques in the treatment of Stage III non-small cell lung cancer. Five patients with significant tumour motion were retrospectively planned on the average 4D-CT dataset with eight different IMRT techniques: three Tomotherapy techniques with different beam-widths, two step-and-shoot (SS-IMRT) with different complexity, one sliding-window (SW-IMRT), and two VMAT techniques (RapidArc and SmartArc). Each plan was calculated on a delivery verification phantom that was mounted on a programmable respiratory motion platform and delivered under the following motion conditions: 1) Static; 2) sinusoidal with 4 different amplitudes; 3) Real Patient Breathing. A standard 3%/3mm gamma analysis compared the sum of all 30 fractions to their corresponding 60Gy/30fx plan. One-way ANOVA was conducted for respiratory motion amplitude and IMRT modality, separately. There were no significant differences amongst the modalities at any amplitude level. However, for individual modalities, there were significant differences amongst different amplitudes except for Tomo-2.5cm (p=0.260). Post-hoc Tukey tests determined that detectable significant differences amongst any motion level, including real-patient breathing, were observed when compared to the 20mm amplitude for all modalities except Tomo-2.5cm and SmartArc. SW-IMRT showed significant differences at 15mm when compared to both static (p=0.033) and 5mm (p=0.008). All methods except for RapidArc averaged out to clinically acceptable gamma pass rates up to 15mm. In conclusion, for motion levels above 15mm, the interplay effect can be clinically unacceptable. However, the interplay effect at these motion levels does not appear to be modality dependent.

Effect of lateral target motion on image registration accuracy in CT-guided helical tomotherapy: a phantom study.

Optimisation of imaging modes for kilovoltage CT (kVCT) used for treatment planning and megavoltage CT (MVCT) image guidance used in ungated helical tomotherapy was investigated for laterally moving targets. Computed tomography images of the QUASAR Respiratory Motion Phantom were acquired without target motion and for lateral motion of the target, with 2-cm peak-to-peak amplitude and a period of 4 s. Reference kVCT images were obtained using a 16-slice CT scanner in standard fast helical CT mode, untagged average CT mode and various post-processed 4D-CT modes (0% phase, average and maximum intensity projection). Three sets of MVCT images with different inter-slice spacings of were obtained on a Hi-Art tomotherapy system with the phantom displaced by a known offset position. Eight radiation therapists performed co-registration of MVCT obtained with 2-, 4- and 6-mm slice spacing and kVCT studies independently for all 15 CT imaging combinations. In the investigated case, the untagged average kVCT and 4-mm slice spacing for the MVCT yielded more accurate registration in the transverse plane. The average residual uncertainty of this combination of imaging procedures was 0.61 +/- 0.16 mm in the longitudinal direction, 0.45 +/- 0.14 mm in the anterior-posterior direction and insignificant in the lateral direction. Manual registration of MVCT-kVCT study pairs is necessary to account for a target in significant lateral motion with respect to bony structures.

Poster - Thurs Eve-18: Performance evaluation of MV CT imaging on the HI ART II tomotherapy unit.

The HI-ART II unit (TomoTherapy Inc., Madison WI) is a modality used by the London Regional Cancer Program (LRCP) for radiation therapy. This machine uses the same source of Megavoltage energy radiation to image (3.5 MV) and to treat (6MV) patients, combining the functionality of a traditional linear accelerator and CT simulator into one unit. Thus, it is possible to assess patient positioning and adjust for anatomy changes just prior to radiation therapy. Unfortunately, at MV energy levels, the physics of radiation interaction limits image quality, and gives rise to an inherent dose limitation concern that enhances noise levels. Therefore, we propose to quantify the image quality produced by the HI-ART II unit using techniques established for kVCT scanner technology. Our study involved the use of three standard phantoms to test image resolution, noise, uniformity, and linearity for a 512 × 512 reconstruction matrix and three scan pitch settings (0.8, 1.6, and 2.4). Results follow: linearity between MV CT number versus relative electron density was observed, noise calculations ranged from 2.15-2.51%, and a distinct central artifact was revealed during uniformity testing. The linearity between MV CT number versus relative electron density implies that MV CT images are highly suitable for dose calculations. MV CT image quality of uniform phantoms were acceptable and demonstrated noise levels higher than those produced by kVCT simulators. Further study is necessary to correct for the central artifact in MV CT images.

Poster - Thurs Eve-40: The potential of using SPECT ventilation information with IMRT for functional lung avoidance in radiotherapy of non small cell lung cancer.

We have investigated the feasibility of using ventilation scans obtained from single photon emission computed tomography (SPECT) in intensity-modulated radiation therapy (IMRT) planning in lung cancer radiotherapy to avoid well functioning lung. We fused SPECT ventilation scans acquired at GE Hawkeye SPECT-CT of ten stage-III lung radiotherapy patients with planning CT in treatment planning system (Pinnacle v8.0, Philips Medical Systems). We automatically segment out 50% and 70% ventilated volumes. For each patient, we generated IMRT plans using nine equally spaced beams with and without avoiding well ventilated volume. They were compared with three beam IMRT plans with beam directions chosen to minimize the mean dose to the ventilated lung volumes, while keeping cord dose below tolerance and dose uniformity in the target. The plans generated using functional lung avoidance information reduces the doses to the functioning lung. With both IMRT avoidance plans, we could not obtain better functional avoidance or lower V-20Gy (volume receiving 20Gy or more) for total lung when the planning target volume (PTV) was surrounded by functional lung volumes. We were able to achieve better ventilated lung avoidance and lower total lung V-20Gy when the PTV is close to, but not surrounded by functioning lung volumes. For patients with the PTV that is far from 50% and 70% functional lung volumes, three-field IMRT spare the ventilated lung as well as nine-field IMRT ventilation avoidance plan, with a lower total lung V20-Gy.

An algorithm for systematic selection of beam directions for IMRT.

Selection of the number of beams and their directions can be an important problem in radiation therapy, especially when a tumor surrounds a critical organ or is surrounded by multiple critical organs. Beam directions, in this sense, are chosen to not only avoid critical organs, but also to achieve better target dose uniformity. In intensity-modulated radiation therapy (IMRT), optimization of beam directions is further complicated due to the dependence of one beam direction on its corresponding beamlet intensities and the beamlet intensities of all other beam directions. The result is an excessively enlarged search space, even when the number of beams is small (two to three). Until now, only a handful of publications exist regarding beam direction optimization in IMRT. Here, we report a new systematic approach that determines a suitable number of "more optimal" beam directions without optimizing a complicated objective function or resorting to brute force. We start by assuming that beam directions chosen for an N-beam plan are candidates for beam directions in the search for an (N + 1)-beam plan. Knowing that beam directions in an N-beam plan are not always the best choices for the (N + 1)-beam plan, we introduce into the beam direction selection process an analysis of the beamlet weights of every beam direction set sampled. If the relative weights of any particular beam compared to other beams are insignificant and hence have no significant effect on the quality of the treatment plan, then we eliminate this beam from the plan. The algorithm terminates basically when the relative weights of the last beam compared to other beams are insignificant or the replacement of an eliminated beam does not improve the plan. This concept was applied to three two-dimensional phantoms and each plan was compared to a standard equally spaced IMRT plan in terms of dose distributions, dose-volume histograms, and objective function values. The results show improvements in both target dose uniformity and critical organ sparing often with a fewer number of beams than standard equally spaced beam plans.

Ia antigen expression in the rat uterus.

Using indirect immunofluorescence and monoclonal antibodies, we have determined the distribution of Ia+ cells in the non-pregnant rat uterus. In cycling animals, Ia+ cells, most of dendritic shape and non-specific esterase negative, were abundant in the connective tissue of the myometrium and throughout the endometrium, especially adjacent to the luminal and glandular epithelia. In contrast, the number of T lymphocytes was very much less and few of these cells expressed Ia antigen. Stromal Ia+ cells were more numerous during estrus than in any other phase of the cycle. Only a few Ia+ cells were seen in neonatal uterine samples, but the numbers increased to approximately adult levels by 32 days of age. Prepubertal glands were consistently negative, but epithelial expression of Ia antigens in adult uteri showed interesting variations. The luminal epithelium was always negative, whereas the glandular epithelial cells often were positive. Glandular staining was quite heterogeneous in individual samples, but most gland profiles were negative or weakly positive during proestrus and estrus and positive during diestrus. Ovariectomized females given different steroid supplements revealed significant hormonal effects. Estrogen alone dramatically increased the numbers of Ia+ stromal cells compared with control samples, but progesterone alone had no effect. However, progesterone given with estrogen abrogated the estrogenic influence. Progesterone alone caused decreased expression of Ia antigens by the glandular epithelium. If the highly-Ia/ cells in the stroma are capable of antigen presentation, these results indicate a significant potential for local antigen processing with the uterine endometrium.

Unusual problems for the physician in managing a hospital patient who received a malicious insulin overdose.

A patient recovering normally from a biopsy and subtotal removal of a malignant brain tumor became severely hypoglycemic on the ward and died. The differential diagnosis eliminated disease as a possible cause, and medication error on the floor was also ruled out. Deliberate administration of a massive dose of insulin intravenously seemed to be the only alternative. A careful investigation supported the likelihood of a criminal act. The patient's wife came under suspicion and was subsequently arrested, charged with murder, and convicted. This sequence of events created three problems that fell outside of our normal professional training and experience as physicians. First, we were slow to suspect foul play in our search for an unusual cause. Second, the steps taken to protect the patient against further risk without denying reasonable rights to family or arousing the suspect's suspicions needed strengthening. Third, even though the occurrence of these events in a hospital allowed an unusual degree of evidence documenting the allegations to be accumulated, key parts of the evidence could not be used. The routine hospital handling of laboratory tests critical to support of the accusations was not sufficient to meet the demands of the legal system, which has its own criteria. We discuss the issues in managing these problems.

Endothelial mitosis during the initial stages of corpus luteum neovascularization in the cycling adult rat.

The initial stages of neovascularization of the corpus luteum were studied in cycling adult rats using light-microscopic autoradiography. The aim of this analysis was to determine whether endothelial mitosis is a factor in this vascular growth and whether there are differences in the amount of mitotic activity in various regions of the ovary. Ovaries were examined at two time intervals: 1-2 hr and 7-8 hr following ovulation. Animals received an intraperitoneal injection of tritiated-thymidine 20 min prior to perfusion fixation of the ovaries. Autoradiographic demonstration of tritiated-thymidine labeling in endothelial nuclei was considered an indication of DNA synthesis preceding mitosis. The percentage of labeled endothelial cells in the ovaries at both time intervals varied according to the region of tissue examined and the stage of differentiation of that region. Stromal vessels were less heavily labeled than thecal vessels. Thecal vessels surrounding growing follicles were more heavily labeled than those surrounding atretic follicles. The heaviest labeling was seen in the developing corpora lutea 7-8 hr following ovulation. Minimal labeling was evident in the corpora lutea which were formed in previous cycles. A regional difference was also detected in the ovarian mesothelium. The portion of the mesothelium overlying ovulated follicles and developing corpora lutea had the greatest percentage of labeled cells. The major findings of this study were: endothelial mitosis was elevated in the initial stages of luteal neovascularization; the heightened endothelial labeling was confined to specific regions of the ovary; and mesothelium in close proximity to the developing corpora lutea also displayed heightened DNA synthesis.