Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

An approach to generate synthetic 4DCT datasets to benchmark Mid-Position implementations.

PURPOSE: The Mid-Position image is constructed from 4DCT data using Deformable Image Registration and can be used as planning CT with reduced PTV volumes. 4DCT datasets currently-available for testing do not provide the corresponding Mid-P images of the datasets. This work describes an approach to generate human-like synthetic 4DCT datasets with the associated Mid-P images that can be used as reference in the validation of Mid-P implementations. METHODS: Twenty synthetic 4DCT datasets with the associated reference Mid-P images were generated from twenty clinical 4DCT datasets. Per clinical dataset, an anchor phase was registered to the remaining nine phases to obtain nine Deformable Vector Fields (DVFs). These DVFs were used to warp the anchor phase in order to generate the synthetic 4DCT dataset and the corresponding reference Mid-P image. Similarly, a reference 4D tumor mask dataset and its corresponding Mid-P tumor mask were generated. The generated synthetic datasets and masks were used to compare and benchmark the outcomes of three independent Mid-P implementations using a set of experiments. RESULTS: The Mid-P images constructed by the three implementations showed high similarity scores when compared to the reference Mid-P images except for one noisy dataset. The biggest difference in the estimated motion amplitudes (-2.6 mm) was noticed in the Superior-Inferior direction. The statistical analysis showed no significant differences among the three implementations for all experiments. CONCLUSION: The described approach and the proposed experiments provide an independent method that can be used in the validation of any Mid-P implementation being developed.

Urethra Sparing With Target Motion Mitigation in Dose-Escalated Extreme Hypofractionated Prostate Cancer Radiotherapy: 7-Year Results From a Phase II Study.

Purpose: To explore whether the rectal distension-mediated technique, harnessing human physiology to achieve intrafractional prostate motion mitigation, enables urethra sparing by inverse dose painting, thus promoting dose escalation with extreme hypofractionated stereotactic ablative radiotherapy (SABR) in prostate cancer. Materials and Methods: Between June 2013 and December 2018, 444 patients received 5 × 9 Gy SABR over 5 consecutive days. Rectal distension-mediated SABR was employed via insertion of a 150-cm3 air-inflated endorectal balloon. A Foley catheter loaded with 3 beacon transponders was used for urethra visualization and online tracking. MRI-based planning using Volumetric Modulated Arc Therapy - Image Guided Radiotherapy (VMAT-IGRT) with inverse dose painting was employed in delivering the planning target volume (PTV) dose and in sculpting exposure of organs at risk (OARs). A 2-mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. All plans fulfilled Dmean ≥45 Gy. Target motion ≥2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of the planned dose delivery. Results: Patient compliance to the rectal distension-mediated immobilization protocol was excellent, achieving reproducible daily prostate localization at a patient-specific retropubic niche. Online tracking recorded ≤1-mm intrafractional target deviations in 95% of treatment sessions, while target realignment in ≥2-mm deviations enabled treatment completion as scheduled in all cases. The cumulative incidence rates of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) toxicities were 5.3% and 1.1%, respectively. The favorable toxicity profile was corroborated by patient-reported quality of life (QOL) outcomes. Median prostate-specific antigen (PSA) nadir by 5 years was 0.19 ng/ml. The cumulative incidence rate of biochemical failure using the Phoenix definition was 2%, 16.6%, and 27.2% for the combined low/favorable-intermediate, unfavorable intermediate, and high-risk categories, respectively. Patients with a PSA failure underwent a 68Ga-labeled prostate-specific membrane antigen (68Ga-PSMA) scan showing a 20.2% cumulative incidence of intraprostatic relapses in biopsy International Society of Urological Pathology (ISUP) grade ≥3. Conclusion: The rectal distension-mediated technique is feasible and well tolerated. Dose escalation to 45 Gy with urethra-sparing results in excellent toxicity profiles and PSA relapse rates similar to those reported by other dose-escalated regimens. The existence of intraprostatic recurrences in patients with high-risk features confirms the notion of a high α/ß ratio in these phenotypes resulting in diminished effectiveness with hypofractionated dose escalation.

Reproducibility and accuracy of a target motion mitigation technique for dose-escalated prostate stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: To quantitate the accuracy, reproducibility and prostate motion mitigation efficacy rendered by a target immobilization method used in an intermediate-risk prostate cancer dose-escalated 5×9Gy SBRT study. MATERIAL AND METHODS: An air-inflated (150 cm3) endorectal balloon and Foley catheter with three electromagnetic beacon transponders (EBT) were used to mitigate and track intra-fractional target motion. A 2 mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. EBT-detected ≥ 2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of planned dose delivery. Geometrical uncertainties were measured with an in-house ESAPI script. RESULTS: Quantitative data were obtained in 886 sessions from 189 patients. Mean PTV dose was 45.8 ± 0.4 Gy (D95 = 40.5 ± 0.4 Gy). A mean of 3.7 ± 1.7 CBCTs were acquired to reach reference position. Mean treatment time was 19.5 ± 12 min, 14.1 ± 11 and 5.4 ± 5.9 min for preparation and treatment delivery, respectively. Target motion of 0, 1-2 and >2 mm/10 min were observed in 59%, 30% and 11% of sessions, respectively. Temporary beam-on hold occurred in 7.4% of sessions, while in 6% a new reference CBCT was required to correct deviations. Hence, all sessions were completed with application of the planned dose. Treatment preparation time > 15 min was significantly associated with the need of a second reference CBCT. Overall systematic and random geometrical errors were in the order of 1 mm. CONCLUSION: The prostate immobilization technique explored here affords excellent accuracy and reproducibility, enabling normal tissue dose sculpting with tight PTV margins.

Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in Patients With Intermediate-Risk Prostate Cancer: Results From the PROSINT Phase 2 Randomized Clinical Trial.

IMPORTANCE: Ultra-high single-dose radiotherapy (SDRT) represents a potential alternative to curative extreme hypofractionated stereotactic body radiotherapy (SBRT) in organ-confined prostate cancer. OBJECTIVE: To compare toxic effect profiles, prostate-specific antigen (PSA) responses, and quality-of-life end points of SDRT vs extreme hypofractionated SBRT. DESIGN, SETTING, AND PARTICIPANTS: The PROSINT single-institution phase 2 randomized clinical trial accrued, between September 2015 and January 2017, 30 participants with intermediate-risk prostate cancer to receive SDRT or extreme hypofractionated SBRT. Androgen deprivation therapy was not permitted. Data were analyzed from March to May 2020. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive 5 × 9 Gy SBRT (control arm) or 24 Gy SDRT (test arm). MAIN OUTCOMES AND MEASURES: The primary end point was toxic effects; the secondary end points were PSA response, PSA relapse-free survival, and patient-reported quality of life measured with the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaires. RESULTS: A total of 30 men were randomized; median (interquartile range) age was 66.3 (61.2-69.9) and 73.6 (64.7-75.9) years for the SBRT and SDRT arms, respectively. Time to appearance and duration of acute and late toxic effects were similar in the 2 trial arms. Cumulative late actuarial urinary toxic effects did not differ for grade 1 (hazard ratio [HR], 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57). Actuarial grade 1 late gastrointestinal (GI) toxic effects were comparable (HR, 0.37; 90% CI, 0.07-1.94) and there were no grade 2 or greater late GI toxic effects. Declines in PSA level to less than 0.5 ng/mL occurred by 36 months in both study arms. No PSA relapses occurred in favorable intermediate-risk disease, while in the unfavorable category, the actuarial 4-year PSA relapse-free survival values were 75.0% vs 64.0% (HR, 0.76; 90% CI, 0.17-3.31) for SBRT vs SDRT, respectively. The EPIC-26 median summary scores for the genitourinary and GI domains dropped transiently at 1 month and returned to pretreatment scores by 3 months in both arms. The IPSS-derived transient late urinary flare symptoms occurred at 9 to 18 months in 20% (90% CI, 3%-37%) of patients receiving SDRT. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial among patients with intermediate-risk prostate cancer, SDRT was safe and associated with low toxicity, and the tumor control and quality-of-life end points closely match the SBRT arm outcomes. Further studies are encouraged to explore indications for SDRT in the cure of prostate cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02570919.

Target motion mitigation promotes high-precision treatment planning and delivery of extreme hypofractionated prostate cancer radiotherapy: Results from a phase II study.

BACKGROUND AND PURPOSE: While favourable long-term outcomes have been reported in organ-confined prostate cancer treated with 5 × 7-8 Gy extreme hypofractionation, dose escalation to 5 × 9-10 Gy improved local control but was associated with unacceptable rates of late rectal and urinary toxicities. The purpose of this study was to explore the feasibility of intra-fractional prostate immobilization in reducing toxicity, to promote dose escalation with extreme hypofractionated radiotherapy in prostate cancer. MATERIAL AND METHODS: 207 patients received 5 consecutive fractions of 9 Gy. An air-inflated (150 cm3) endorectal balloon and an intraurethral Foley catheter with 3 beacon transponders were used to immobilize the prostate and monitor intra-fractional target motion. VMAT-IGRT with inverse dose-painting was employed in delivering the PTV dose and in sculpting exposure of normal organs at risk to fulfil dose-volume constraints. RESULTS: Introduction of air-filled balloon induced repeatable rectum/prostate complex migration from its resting position to a specific retropubic niche, affording the same 3D anatomical configuration daily. Intra-fractional target deviations ≤1 mm occurred in 95% of sessions, while target realignment in ≥2 mm deviations enabled treatment completion as scheduled. Nadir PSA at median 54 months follow-up was 0.19 ng/mL, and bRFS was 100%, 92.4% and 71.4% in low-, intermediate- and high-risk categories, respectively. Late Grade 2 GU and GI toxicities were 2.9% and 2.4%, respectively. No adverse changes in patient-reported quality of life scores were observed. CONCLUSION: The unique spatial configuration of this prostate motion mitigation protocol enabled precise treatment planning and delivery that optimized outcomes of ultra-high 5 × 9 Gy hypofractionated radiotherapy of organ-confined prostate cancer.

Developments in zebrafish avatars as radiotherapy sensitivity reporters - towards personalized medicine.

BACKGROUND: Whereas the role of neoadjuvant radiotherapy in rectal cancer is well-established, the ability to discriminate between radioresistant and radiosensitive tumors before starting treatment is still a crucial unmet need. Here we aimed to develop an in vivo test to directly challenge living cancer cells to radiotherapy, using zebrafish xenografts. METHODS: We generated zebrafish xenografts using colorectal cancer cell lines and patient biopsies without in vitro passaging, and developed a fast radiotherapy protocol consisting of a single dose of 25 Gy. As readouts of the impact of radiotherapy we analyzed proliferation, apoptosis, tumor size and DNA damage. FINDINGS: By directly comparing isogenic cells that only differ in the KRASG13D allele, we show that it is possible to distinguish radiosensitive from radioresistant tumors in zebrafish xenografts, even in polyclonal tumors, in just 4 days. Most importantly, we performed proof-of-concept experiments using primary rectum biopsies, where clinical response to neoadjuvant chemoradiotherapy correlates with induction of apoptosis in their matching zebrafish Patient-Derived Xenografts-Avatars. INTERPRETATION: Our work opens the possibility to predict tumor responses to radiotherapy using the zebrafish Avatar model, sparing valuable therapeutic time and unnecessary toxicity.

Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer.

Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

In silico comparison of photons versus carbon ions in single fraction therapy of lung cancer.

PURPOSE: Stereotactic body image guided radiation therapy (SBRT) shows good results for lung cancer treatment. Better normal tissue sparing might be achieved with scanned carbon ion therapy (PT). Therefore an in silico trial was conducted to find potential advantages of and patients suited for PT. METHODS: For 19 patients treated with SBRT, PT plans were calculated on 4D-CTs with simulated breathing motion. Prescribed single fraction dose was 24Gy and OAR constraints used for photon planning were respected. Motion was mitigated by rescanning and range-adapted ITVs. Doses were compared to the original SBRT plans. RESULTS: CTV coverage was the same in SBRT and PT. The field-specific PTV including range margins for PT was 1.5 (median, 25-75% 1.3-2.1) times larger than for SBRT. Nevertheless, maximum point dose and mean dose in OARs were higher in SBRT by 2.8 (1.6-3.7) Gy and 0.7 (0.3-1.6) Gy, respectively. Patients with a CTV >2.5cc or with multiple lung lesions showed larger differences in OAR doses in favor of PT. CONCLUSIONS: Patients receive less dose in critical OARs such as heart, spinal cord, esophagus, trachea and aorta with PT, while maintaining the same target coverage. Patients with multiple or larger lesions are particularly suited for PT.

The effect of age in breast conserving therapy: a retrospective analysis on pathology and clinical outcome data.

BACKGROUND AND PROPOSE: Age is an important prognostic marker of patient outcome after breast conserving therapy; however, it is not clear how age affects the outcome. This study aimed to explore the relationship between age with the cell quantity and the radiosensitivity of microscopic disease (MSD) in relation to treatment outcome. MATERIALS AND METHODS: We employed a treatment simulation framework which contains mathematic models for describing the load and spread of MSD based on a retrospective cohort of breast pathology specimens, a surgery simulation model for estimating the remaining MSD quantity and a tumor control probability model for predicting the risk of local recurrence following radiotherapy. RESULTS: The average MSD cell quantities around the primary tumor in younger (age⩽50years) and older patients were estimated at 1.9∗10(8)cells and 8.4∗10(7)cells, respectively (P<0.01). Following surgical simulation, these numbers decreased to 2.0∗10(7)cells and 1.3∗10(7)cells (P<0.01). Younger patients had smaller average surgical resection volume (118.9cm(3)) than older patients (162.9cm(3), P<0.01) but larger estimated radiosensitivity of MSD cells (0.111Gy(-1) versus 0.071Gy(-1), P<0.01). CONCLUSION: The higher local recurrence rate in younger patients could be explained by larger clonogenic microscopic disease cell quantity, even though the microscopic disease cells were found to be more radiosensitive.

On the robustness of VMAT-SABR treatment plans against isocentre positioning uncertainties.

BACKGROUND: To appraise the robustness of VMAT dose distributions against uncertainties in the positioning of the patients when single fraction SABRT treatments are planned. METHODS: A set of 18 patients (8 lung, 5 brain, 5 spinal or para-spinal) treated with VMAT in a single fraction of 24Gy were retrospectively analyzed. All approved plans were re-calculated by applying shifts to the isocentre of ±0.5, ±1, ±1.5, ±2 and ±3 mm along the primary X, Y and Z axes. Dose calculations were performed with the AAA and the Acuros engines. Quantitative analysis of DVH was performed on a total of 36 references (18 patients with AAA, 18 with Acuros) and 1080 re-calculated plans to measure the potential degree of deterioration of the plans according to the simulated errors. RESULTS: The dose to the CTV was essentially not affected by the isocenter shifts in all cases. Concerning PTV, The main impact was observed on the near-to-minimum dose D99%. No relevant impact was observed on organs at risk in the case of lung patients. In the case of patients treated in the spinal or para-spinal region, the near-to-maximum dose to the spine showed, in the worst scenario, referring to Acuros calculation, a potential average increase of 0.3Gy with a maximum of 1.9Gy (from 10.3 to 12.2 Gy) or 18%. This was partially mitigated to 12% with 1 mm and to 5% with 0.5 mm shifts. CONCLUSIONS: The study showed that shifts in the position of the isocenter as large as 3 mm tend to have modest impacts on the quality of the VMAT plans, scored by means of conventional DVH parameters. From the data shown, the VMAT approach should be considered adequately robust for single fraction SABR.

A simulation framework for modeling tumor control probability in breast conserving therapy.

BACKGROUND AND PURPOSE: Microscopic disease (MSD) left after tumorectomy is a major cause of local recurrence in breast conserving therapy (BCT). However, the effect of microscopic disease and RT dose on tumor control probability (TCP) was seldom studied quantitatively. A simulation framework was therefore constructed to explore the relationship between tumor load, radiation dose and TCP. MATERIALS AND METHODS: First, we modeled total disease load and microscopic spread with a pathology dataset. Then we estimated the remaining disease load after tumorectomy through surgery simulation. The Webb-Nahum TCP model was extended by clonogenic cell fraction to model the risk of local recurrence. The model parameters were estimated by fitting the simulated results to the observations in two clinical trials. RESULTS: Higher histopathology grade has a strong correlation with larger MSD cell quantity. On average 12.5% of the MSD cells remained in the patient's breast after surgery but varied considerably among patients (0-100%); illustrating the role of radiotherapy. A small clonogenic cell fraction was optimal in our model (one in every 2.7*10(6)cells). The mean radiosensitivity was estimated at 0.067Gy(-1) with standard deviation of 0.022Gy(-1). CONCLUSION: A relationship between radiation dose and TCP was established in a newly designed simulation framework with detailed disease load, surgery and radiotherapy models.

Combined recipe for clinical target volume and planning target volume margins.

PURPOSE: To develop a combined recipe for clinical target volume (CTV) and planning target volume (PTV) margins. METHODS AND MATERIALS: A widely accepted PTV margin recipe is M(geo) = aΣ(geo) + bσ(geo), with Σ(geo) and σ(geo) standard deviations (SDs) representing systematic and random geometric uncertainties, respectively. On the basis of histopathology data of breast and lung tumors, we suggest describing the distribution of microscopic islets around the gross tumor volume (GTV) by a half-Gaussian with SD Σ(micro), yielding as possible CTV margin recipe: M(micro) = ƒ(N(i)) × Σ(micro), with N(i) the average number of microscopic islets per patient. To determine ƒ(N(i)), a computer model was developed that simulated radiation therapy of a spherical GTV with isotropic distribution of microscopic disease in a large group of virtual patients. The minimal margin that yielded D(min) <95% in maximally 10% of patients was calculated for various Σ(micro) and N(i). Because Σ(micro) is independent of Σ(geo), we propose they should be added quadratically, yielding for a combined GTV-to-PTV margin recipe: M(GTV-PTV) = √{[aΣ(geo)](2) + [ƒ(N(i))Σ(micro)](2)} + bσ(geo). This was validated by the computer model through numerous simultaneous simulations of microscopic and geometric uncertainties. RESULTS: The margin factor ƒ(N(i)) in a relevant range of Σ(micro) and N(i) can be given by: ƒ(N(i)) = 1.4 + 0.8log(N(i)). Filling in the other factors found in our simulations (a = 2.1 and b = 0.8) yields for the combined recipe: M(GTV-PTV) = √({2.1Σ(geo)}(2) + {[1.4 + 0.8log(N(i))] × Σ(micro)}(2)) + 0.8σ(geo). The average margin difference between the simultaneous simulations and the above recipe was 0.2 ± 0.8 mm (1 SD). Calculating M(geo) and M(micro) separately and adding them linearly overestimated PTVs by on average 5 mm. Margin recipes based on tumor control probability (TCP) instead of D(min) criteria yielded similar results. CONCLUSIONS: A general recipe for GTV-to-PTV margins is proposed, which shows that CTV and PTV margins should be added in quadrature instead of linearly.

Microscopic disease extensions as a risk factor for loco-regional recurrence of NSCLC after SBRT.

PURPOSE: Stereotactic body radiotherapy (SBRT) is a highly conformal technique that allows a more accurate irradiation of lung tumors. However, a highly conformal dose distribution may underdose undetected microscopic disease extensions (MDE) near the tumor leading to loco-regional failure in tumor control. The purpose of the current work is to assess the risk of loco-regional failure in SBRT by analyzing pre-treatment scans. METHODS AND MATERIALS: A model to predict the risk of occurrence of MDE from pretreatment images was developed based on pathology samples of 47 lung cancer patients. This model was used to assess the outcome of 238 SBRT treatments. RESULTS: Patients with high risk of MDE presence showed significantly lower 2-year loco-regional control (82.0% vs. 91.8%) and shorter time to loco-regional failure (8.4 months vs. 20.7 months) than low risk patients. The minimum dose delivered in the volume surrounding the GTV affected the model predictive power. The model remained predictive for patients who received less than 31 Gy in that volume. For patients who received larger doses, the MDE risk classification was not significant. CONCLUSIONS: The results show that MDEs are, at least partially, responsible of loco-regional failure in highly conformal radiotherapy. This information could be used to optimize dose distributions.

Impact of negative margin width on local recurrence in breast conserving therapy.

BACKGROUND AND PURPOSE: This study aims to explain the unexpected weak association between the width of the negative surgical margin and the risk of local recurrence in breast conserving therapy. MATERIALS AND METHODS: We utilized a classical tumor-control probability (TCP) model to estimate the risk of local recurrence, considering the heterogeneity of microscopic disease spread observed around the invasive index tumor in a pathology dataset (N=60). The estimated result was compared with the true risk observed in the EORTC boost-versus-no-boost trial (N=1616). RESULTS: The disease volume beyond any given distance from the edge of the index tumor varied considerably among patients. Adopting this disease volume variation in the TCP model accurately reproduced the local recurrence rate as function of surgical margin width in the boost-versus-no-boost trial (Pearson's correlation coefficients are 0.652 and 0.862, and significant at the 0.05 and 0.01 level for absence and presence of a radiation boost, respectively). CONCLUSIONS: The impact of a negative margin width on local recurrence is limited due to the large variation of microscopic disease that can reach large quantities beyond any given distance from the edge of the index tumor across the patient population of breast-conserving therapy.

In aqua vivo EPID dosimetry.

PURPOSE: At the Netherlands Cancer Institute--Antoni van Leeuwenhoek Hospital in vivo dosimetry using an electronic portal imaging device (EPID) has been implemented for almost all high-energy photon treatments of cancer with curative intent. Lung cancer treatments were initially excluded, because the original back-projection dose-reconstruction algorithm uses water-based scatter-correction kernels and therefore does not account for tissue inhomogeneities accurately. The aim of this study was to test a new method, in aqua vivo EPID dosimetry, for fast dose verification of lung cancer irradiations during actual patient treatment. METHODS: The key feature of our method is the dose reconstruction in the patient from EPID images, obtained during the actual treatment, whereby the images have been converted to a situation as if the patient consisted entirely of water; hence, the method is termed in aqua vivo. This is done by multiplying the measured in vivo EPID image with the ratio of two digitally reconstructed transmission images for the unit-density and inhomogeneous tissue situation. For dose verification, a comparison is made with the calculated dose distribution with the inhomogeneity correction switched off. IMRT treatment verification is performed for each beam in 2D using a 2D γ evaluation, while for the verification of volumetric-modulated arc therapy (VMAT) treatments in 3D a 3D γ evaluation is applied using the same parameters (3%, 3 mm). The method was tested using two inhomogeneous phantoms simulating a tumor in lung and measuring its sensitivity for patient positioning errors. Subsequently five IMRT and five VMAT clinical lung cancer treatments were investigated, using both the conventional back-projection algorithm and the in aqua vivo method. The verification results of the in aqua vivo method were statistically analyzed for 751 lung cancer patients treated with IMRT and 50 lung cancer patients treated with VMAT. RESULTS: The improvements by applying the in aqua vivo approach are considerable. The percentage of γ values ≤1 increased on average from 66.2% to 93.1% and from 43.6% to 97.5% for the IMRT and VMAT cases, respectively. The corresponding mean γ value decreased from 0.99 to 0.43 for the IMRT cases and from 1.71 to 0.40 for the VMAT cases, which is similar to the accepted clinical values for the verification of IMRT treatments of prostate, rectum, and head-and-neck cancers. The deviation between the reconstructed and planned dose at the isocenter diminished on average from 5.3% to 0.5% for the VMAT patients and was almost the same, within 1%, for the IMRT cases. The in aqua vivo verification results for IMRT and VMAT treatments of a large group of patients had a mean γ of approximately 0.5, a percentage of γ values ≤1 larger than 89%, and a difference of the isocenter dose value less than 1%. CONCLUSIONS: With the in aqua vivo approach for the verification of lung cancer treatments (IMRT and VMAT), we can achieve results with the same accuracy as obtained during in vivo EPID dosimetry of sites without large inhomogeneities.

Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features.

PURPOSE: One major uncertainty in radiotherapy planning of non-small-cell lung cancer concerns the definition of the clinical target volume (CTV), meant to cover potential microscopic disease extension (MDE) around the macroscopically visible tumor. The primary aim of this study was to establish pretreatment risk factors for the presence of MDE. The secondary aim was to establish the impact of these factors on the accuracy of positron emission tomography (PET) and computed tomography (CT) to assess the total tumor-bearing region at pathologic examination (CTV(path)). METHODS AND MATERIALS: 34 patients with non-small-cell lung cancer who underwent CT and PET before lobectomy were included. Specimens were examined microscopically for MDE. The gross tumor volume (GTV) on CT and PET (GTV(CT) and GTV(PET), respectively) was compared with the GTV and the CTV at pathologic examination, tissue deformations being taken into account. Using multivariate logistic regression, image-based risk factors for the presence of MDE were identified, and a prediction model was developed based on these factors. RESULTS: MDE was found in 17 of 34 patients (50%). The MDE did not exceed 26 mm in 90% of patients. In multivariate analysis, two parameters (mean CT tumor density and GTV(CT)) were significantly associated with MDE. The area under the curve of the two-parameter prediction model was 0.86. Thirteen tumors (38%, 95% CI: 24-55%) were identified as low risk for MDE, being potential candidates for reduced-intensity therapy around the GTV. In the low-risk group, the effective diameter of the GTV(CT/PET) accurately represented the CTV(path). In the high-risk group, GTV(CT/PET) underestimated the CTV(path) with, on average, 19.2 and 26.7 mm, respectively. CONCLUSIONS: CT features have potential to predict the presence of MDE. Tumors identified as low risk of MDE show lower rates of disease around the GTV than do high-risk tumors. Both CT and PET accurately visualize the CTV(path) in low-risk tumors but underestimate it in high-risk tumors.

The impact of microscopic disease on the tumor control probability in non-small-cell lung cancer.

PURPOSE: To indicate which clinical target volume (CTV) margin (if any) is needed for an adequate treatment of non-small-cell lung cancer (NSCLC) using either 3D conformal or stereotactic radiotherapy, taking the distribution of the microscopic disease extension (MDE) into account. METHODS AND MATERIALS: On the basis of the linear-quadratic biological model, a Monte-Carlo simulation was used to study the impact of MDE and setup deviations on the tumor control probability (TCP) after typical 3D conformal and stereotactic irradiation techniques. Setup deviations were properly accounted for in the planning target volume (PTV) margin. Previously measured distributions of MDE outside the macroscopic tumor in NSCLC patients were used. The dependence of the TCP on the CTV margins was quantified. RESULTS: The presence of MDE had a demonstratable influence on the TCP in both the 3D conformal and the stereotactic technique when no CTV margins were employed. The impact of MDE on the TCP values was greater in the 3D conformal scenario (67% TCP with MDE; 84% TCP without MDE) than for stereotactic radiotherapy (91% TCP with MDE; 100% TCP without MDE). Accordingly, an increase of the CTV margin had the greatest impact for the 3D conformal technique. Larger setup errors, with appropriate PTV margins, lead to an increase in TCP for both techniques, showing the interdependence of CTV and PTV margins. CONCLUSIONS: MDE may not always be eradicated by the beam penumbra or existing PTV margins using either 3D conformal or stereotactic radiotherapy. Nonetheless, TCP modeling indicates an overall local control rate above 90% for the stereotactic technique, while a non-zero CTV margin is recommended for better local control of MDE when using the 3D conformal technique.

Simplifying EPID dosimetry for IMRT treatment verification.

PURPOSE: Electronic portal imaging devices (EPIDs) are increasingly used for IMRT dose verification, both pretreatment and in vivo. In this study, an earlier developed backprojection model has been modified to avoid the need for patient-specific transmission measurements and, consequently, leads to a faster procedure. METHODS: Currently, the transmission, an essential ingredient of the backprojection model, is estimated from the ratio of EPID measurements with and without a phantom/patient in the beam. Thus, an additional irradiation to obtain "open images" under the same conditions as the actual phantom/patient irradiation is required. However, by calculating the transmission of the phantom/patient in the direction of the beam instead of using open images, this extra measurement can be avoided. This was achieved by using a model that includes the effect of beam hardening and off-axis dependence of the EPID response on photon beam spectral changes. The parameters in the model were empirically obtained by performing EPID measurements using polystyrene slab phantoms of different thickness in 6, 10, and 18 MV photon beams. A theoretical analysis to verify the sensitivity of the model with patient thickness changes was performed. The new model was finally applied for the analysis of EPID dose verification measurements of step-and-shoot IMRT treatments of head and neck, lung, breast, cervix, prostate, and rectum patients. All measurements were carried out using Elekta SL20i linear accelerators equipped with a hydrogenated amorphous silicon EPID, and the IMRT plans were made using PINNACLE software (Philips Medical Systems). RESULTS: The results showed generally good agreement with the dose determined using the old model applying the measured transmission. The average differences between EPID-based in vivo dose at the isocenter determined using either the new model for transmission and its measured value were 2.6 +/- 3.1%, 0.2 +/- 3.1%, and 2.2 +/- 3.9% for 47 patients treated with 6, 10, and 18 MV IMRT beams, respectively. For the same group of patients, the differences in mean gamma analysis (3% maximum dose, 3 mm) were 0.16 +/- 0.26%, 0.21 +/- 0.24%, and 0.02 +/- 0.12%, respectively. For a subgroup of 11 patients, pretreatment verification was also performed, showing similar dose differences at the isocenter: -1.9 +/- 0.9%, -1.4 +/- 1.2%, and -0.4 +/- 2.4%, with somewhat lower mean gamma difference values: 0.01 +/- 0.09%, 0.01 +/- 0.07%, and -0.09 +/- 0.10%, respectively. Clinical implementation of the new model would save 450 h/yr spent in measurement of open images. CONCLUSIONS: It can be concluded that calculating instead of measuring the transmission leads to differences in the isocenter dose generally smaller than 2% (2.6% for 6 MV photon beams for in vivo dose) and yielded only slightly higher gamma-evaluation parameter values in planes through the isocenter. Hence, the new model is suitable for clinical implementation and measurement of open images can be omitted.

3D Dosimetric verification of volumetric-modulated arc therapy by portal dosimetry.

BACKGROUND AND PURPOSE: To demonstrate the feasibility of back-projection portal dosimetry for accurate 3D dosimetric verification of volumetric-modulated arc therapy (VMAT), pre-treatment as well as in vivo. MATERIALS AND METHODS: Several modifications to our existing approach were implemented to make the method applicable to VMAT: (i) gantry angle-resolved data acquisition, (ii) calculation of the patient transmission, (iii) compensation for detector 'flex' and (iv) 3D dose reconstruction and evaluation. RESULTS: Planned and EPID-(Electronic Portal Image Detector)-reconstructed dose distributions show good agreement for pre-treatment verification of two prostate, a stereotactic lung and a head-and-neck VMAT plan and for in vivo verification of VMAT treatments of prostate and lung cancer. Averaged over pre-treatment verifications, planned and measured isocentre dose ratios were -1.2% (range [-4.7%,1.8%]). 3D gamma analysis (3% maximum dose, 3mm) revealed mean gamma gamma(mean)=0.37 [0.34,0.39], maximum 1% gamma gamma(1%)=0.72 [0.66,0.81] and percentage of points with gamma1 P(gamma)(1)=99% [97%,100%]. For in vivo verification, the average isocentre dose ratio was -1.2% [-0.8%,-1.7%], gamma(mean)=0.52 [0.40,0.64], gamma(1%)=0.92 [0.76,1.08] and P(gamma)(1)=96% [93%,100%]. CONCLUSIONS: Our portal dosimetry method was successfully adapted for verification of VMAT treatments, pre-treatment as well as in vivo.