An Analysis of Clinical Toxic Effects and Quality of Life as a Function of Radiation Dose and Volume After Lung Stereotactic Body Radiation Therapy.

PURPOSE: To analyze clinical toxicity and quality-of-life (QOL) outcomes among patients with stage I non-small cell lung cancer (NSCLC) after stereotactic body radiation therapy (SBRT) as a function of radiation dose and volume parameters. METHODS AND MATERIALS: In this institutional review board-approved study, 55 patients with stage I NSCLC who received SBRT (12 Gy × 4) and completed QOL forms were analyzed. Clinical symptoms and QOL outcomes were measured at baseline and at 3, 6, 12, 18, 24, and 36 months after SBRT. Clinical toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0. Quality of life was followed using the validated Functional Assessment of Cancer Therapy-Lung-Trial Outcome Index (FACT-L-TOI) instrument. Dosimetric parameters including the mean lung radiation dose and the volume of normal lung receiving greater than 5, 10, 13, or 20 Gy (V5, V10, V13, and V20) were measured from the radiation treatment plan. Student t tests and Pearson correlation analyses were used to examine the relationships between radiation lung metrics and clinically meaningful changes in QOL and/or clinical toxic effects. The Kaplan-Meier method was used to estimate rates of local control (LC), disease-free survival (DFS), and overall survival (OS). RESULTS: With a median follow-up of 24 months, the 3-year LC, DFS, and OS were 93%, 65%, and 84%, respectively, with a 5.5% rate of grade-3 toxic effects and no grade 4 or 5 toxic effects. Clinically meaningful declines in patient-reported QOL (FACT-L-TOI, lung cancer subscale, physical well-being, and/or functional well-being) posttreatment significantly correlated with increased dosimetric parameters such as V10, V13, and V20. CONCLUSION: Although lung SBRT was associated with excellent LC and minimal clinical toxic effects for early-stage NSCLC, clinically meaningful declines in QOL were significantly correlated with increasing lung dose and volume parameters.

An automated dose tracking system for adaptive radiation therapy.

BACKGROUND AND OBJECTIVE: The implementation of adaptive radiation therapy (ART) into routine clinical practice is technically challenging and requires significant resources to perform and validate each process step. The objective of this report is to identify the key components of ART, to illustrate how a specific automated procedure improves efficiency, and to facilitate the routine clinical application of ART. METHODS: Data was used from patient images, exported from a clinical database and converted to an intermediate format for point-wise dose tracking and accumulation. The process was automated using in-house developed software containing three modularized components: an ART engine, user interactive tools, and integration tools. The ART engine conducts computing tasks using the following modules: data importing, image pre-processing, dose mapping, dose accumulation, and reporting. In addition, custom graphical user interfaces (GUIs) were developed to allow user interaction with select processes such as deformable image registration (DIR). A commercial scripting application programming interface was used to incorporate automated dose calculation for application in routine treatment planning. Each module was considered an independent program, written in C++or C#, running in a distributed Windows environment, scheduled and monitored by integration tools. RESULTS: The automated tracking system was retrospectively evaluated for 20 patients with prostate cancer and 96 patients with head and neck cancer, under institutional review board (IRB) approval. In addition, the system was evaluated prospectively using 4 patients with head and neck cancer. Altogether 780 prostate dose fractions and 2586 head and neck cancer dose fractions went processed, including DIR and dose mapping. On average, daily cumulative dose was computed in 3 h and the manual work was limited to 13 min per case with approximately 10% of cases requiring an additional 10 min for image registration refinement. CONCLUSIONS: An efficient and convenient dose tracking system for ART in the clinical setting is presented. The software and automated processes were rigorously evaluated and validated using patient image datasets. Automation of the various procedures has improved efficiency significantly, allowing for the routine clinical application of ART for improving radiation therapy effectiveness.

A novel approach for evaluation of prostate deformation and associated dosimetric implications in IGRT of the prostate.

PURPOSE: Prostate deformation is assumed to be a secondary correction and is typically ignored in the planning target volume (PTV) margin calculations. This assumption needs to be tested, especially when planning margins are reduced with daily image-guidance. In this study, deformation characteristics of the prostate and seminal vesicles were determined, and the dosimetric impact on treatment plans with different PTV margins was investigated. METHODS: Ten prostate cancer patients were retrospectively selected for the study, each with three fiducial markers implanted in the prostate. Two hundred CBCT images were registered to respective planning CT images using a B-spline-based deformable image registration (DIR) software. A manual bony anatomy-based match was first applied based on the alignment of the pelvic bones and fiducial landmarks. DIR was then performed. For each registration, deformation vector fields (DVFs) of the prostate and seminal vesicles (SVs) were quantified using deformation-volume histograms. In addition, prostate rotation was evaluated and compared with prostate deformation. For a patient demonstrating small and large prostate deformations, target coverage degradation was analyzed in each of three treatment plans with PTV margins of 10 mm (6 mm at the prostate/rectum interface), as well as 5, and 3 mm uniformly. RESULTS: Deformation of the prostate was most significant in the anterior direction. Maximum prostate deformation of greater than 10, 5, and 3 mm occurred in 1%, 17%, and 76% of the cases, respectively. Based on DVF-histograms, DVF magnitudes greater than 5 and 3 mm occurred in 2% and 27% of the cases, respectively. Deformation of the SVs was most significant in the posterior direction, and it was greater than 5 and 3 mm in 7.5% and 44.9% of the cases, respectively. Prostate deformation was found to be poorly correlated with rotation. Fifty percent of the cases showed rotation with negligible deformation and 7% of the cases showed significant deformation with minimal rotation (<3°). Average differences in the D95 dose to the prostate+SVs between the planning CT and CBCT images was 0.4%±0.5%, 3.0%±2.8%, and 6.6%±6.1%, respectively, for the plans with 10/6, 5, and 3 mm margins. For the case with both a large degree of prostate deformation (≈10% of the prostate volume) and rotation (≈8°), D95 was reduced by 0.5%±0.1%, 6.8%±0.6%, and 20.9%±1.6% for 10/6, 5, and 3 mm margin plans, respectively. For the case with large prostate deformation but negligible rotation (<1°), D95 was reduced by 0.4±0.3, 3.9±1.0, and 11.5±2.5 for 10/6, 5, and 3 mm margin plans, respectively. CONCLUSIONS: Prostate deformation over a course of fractionated prostate radiotherapy may not be insignificant and may need to be accounted for in the planning margin design. A consequence of these results is that use of highly reduced planning margins must be viewed with caution.

Evaluation of multiple image-based modalities for image-guided radiation therapy (IGRT) of prostate carcinoma: a prospective study.

PURPOSE: Setup errors and prostate intrafraction motion are main sources of localization uncertainty in prostate cancer radiation therapy. This study evaluates four different imaging modalities 3D ultrasound (US), kV planar images, cone-beam computed tomography (CBCT), and implanted electromagnetic transponders (Calypso/Varian) to assess inter- and intrafraction localization errors during intensity-modulated radiation therapy based treatment of prostate cancer. METHODS: Twenty-seven prostate cancer patients were enrolled in a prospective IRB-approved study and treated to a total dose of 75.6 Gy (1.8 Gy/fraction). Overall, 1100 fractions were evaluated. For each fraction, treatment targets were localized using US, kV planar images, and CBCT in a sequence defined to determine setup offsets relative to the patient skin tattoos, intermodality differences, and residual errors for each patient and patient cohort. Planning margins, following van Herk's formalism, were estimated based on error distributions. Calypso-based localization was not available for the first eight patients, therefore centroid positions of implanted gold-seed markers imaged prior to and immediately following treatment were used as a motion surrogate during treatment. For the remaining 19 patients, Calypso transponders were used to assess prostate intrafraction motion. RESULTS: The means (µ), and standard deviations (SD) of the systematic (Σ) and random errors (σ) of interfraction prostate shifts (relative to initial skin tattoo positioning), as evaluated using CBCT, kV, and US, averaged over all patients and fractions, were: [µ CBCT = (-1.2, 0.2, 1.1) mm, Σ CBCT = (3.0, 1.4, 2.4) mm, σ CBCT = (3.2, 2.2, 2.5) mm], [µkV = (-2.9, -0.4, 0.5) mm, Σ kV = (3.4, 3.1, 2.6) mm, σ kV = (2.9, 2.0, 2.4) mm], and [µ US = (-3.6, -1.4, 0.0) mm, Σ US = (3.3, 3.5, 2.8) mm, σ US = (4.1, 3.8, 3.6) mm], in the anterior-posterior (A/P), superior-inferior (S/I), and the left-right (L/R) directions, respectively. In the treatment protocol, adjustment of couch was guided by US images. Residual setup errors as assessed by kV images were found to be: µ residual = (-0.4, 0.2, 0.2) mm, Σ residual = (1.0, 1.0,0.7) mm, and σ residual = (2.5, 2.3, 1.8) mm. Intrafraction prostate motion, evaluated using electromagnetic transponders, was: µ intrafxn = (0.0, 0.0, 0.0) mm, Σ intrafxn = (1.3, 1.5, 0.6) mm, and σ intrafxn = (2.6, 2.4, 1.4) mm. Shifts between pre- and post-treatment kV images were: µ kV(post-pre) = (-0.3, 0.8, -0.2), Σ kV(post-pre) = (2.4, 2.7, 2.1) mm, and σ kV(post-pre) = (2.7, 3.2, 3.1) mm. Relative to skin tattoos, planning margins for setup error were within 10-11 mm for all image-based modalities. The use of image guidance was shown to reduce these margins to less than 5 mm. Margins to compensate for both residual setup (interfraction) errors as well as intrafraction motion were 6.6, 6.8, and 3.9 mm in the A/P, S/I, and L/R directions, respectively. CONCLUSIONS: Analysis of interfraction setup errors, performed with US, CBCT, planar kV images, and electromagnetic transponders, from a large dataset revealed intermodality shifts were comparable (within 3-4 mm). Interfraction planning margins, relative to setup based on skin marks, were generally within the 10 mm prostate-to-planning target volume margin used in our clinic. With image guidance, interfraction residual planning margins were reduced to approximately less than 4 mm. These findings are potentially important for dose escalation studies using smaller margins to better protect normal tissues.

Dissociation kinetics of an enzyme-inhibitor system using single-molecule force measurements.

We report on an improved method to interpret single molecule dissociation measurements using atomic force microscopy. We describe an easy to use methodology to reject nonspecific binding events, as well as estimating the number of multiple binding events. The method takes nonlinearities in the force profiles into account that result from the deformation of the used polymeric linkers. This new method is applied to a relevant enzyme-inhibitor system, latent matrix metalloprotease 9 (ProMMP-9, a gelatinase), and its inhibitor, tissue inhibitor of metalloproteases 1 (TIMP 1), which are important players in cancer metastasis. Our method provides a measured kinetic off-rate of 0.010 ± 0.003 s(-1) for the dissociation of ProMMP9 and TIMP1, which is consistent with values measured by ensemble methods.