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.

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.

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.

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.

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.

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.

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.

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.

Feasibility of pathology-correlated lung imaging for accurate target definition of lung tumors.

PURPOSE: To accurately define the gross tumor volume (GTV) and clinical target volume (GTV plus microscopic disease spread) for radiotherapy, the pretreatment imaging findings should be correlated with the histopathologic findings. In this pilot study, we investigated the feasibility of pathology-correlated imaging for lung tumors, taking into account lung deformations after surgery. METHODS AND MATERIALS: High-resolution multislice computed tomography (CT) and positron emission tomography (PET) scans were obtained for 5 patients who had non-small-cell lung cancer (NSCLC) before lobectomy. At the pathologic examination, the involved lung lobes were inflated with formalin, sectioned in parallel slices, and photographed, and microscopic sections were obtained. The GTVs were delineated for CT and autocontoured at the 42% PET level, and both were compared with the histopathologic volumes. The CT data were subsequently reformatted in the direction of the macroscopic sections, and the corresponding fiducial points in both images were compared. Hence, the lung deformations were determined to correct the distances of microscopic spread. RESULTS: In 4 of 5 patients, the GTV(CT) was, on average, 4 cm(3) ( approximately 53%) too large. In contrast, for 1 patient (with lymphangitis carcinomatosa), the GTV(CT) was 16 cm(3) ( approximately 40%) too small. The GTV(PET) was too small for the same patient. Regarding deformations, the volume of the well-inflated lung lobes on pathologic examination was still, on average, only 50% of the lobe volume on CT. Consequently, the observed average maximal distance of microscopic spread (5 mm) might, in vivo, be as large as 9 mm. CONCLUSIONS: Our results have shown that pathology-correlated lung imaging is feasible and can be used to improve target definition. Ignoring deformations of the lung might result in underestimation of the microscopic spread.

Prospective study on late renal toxicity following postoperative chemoradiotherapy in gastric cancer.

PURPOSE: Postoperative chemoradiotherapy in gastric cancer improves locoregional control and survival. Reports on late toxicity, however, have been scarce thus far. Because renal toxicity is one of the most serious late complications in upper abdominal radiotherapy, we prospectively analyzed kidney function in patients who underwent postoperative chemoradiotherapy for gastric cancer. PATIENTS AND METHODS: In 44 patients, Tc99m-thiatide renography was performed before and at regular intervals after postoperative chemoradiotherapy. The left-to-right (L/R) ratio was used as an index of the relative kidney function. Mean L/R values were calculated for four follow-up time intervals. For all patients, kidney V20 (percentage of the volume of the kidney that received more than 20 Gy) and mean dose of both kidneys were retrieved from the three-dimensional dose-volume histograms. RESULTS: We observed a progressive decrease in left renal function of 11% (p = 0.012) after 6 months, up to 52% (p < 0.001) after >18 months. The V20 (left kidney) and mean left kidney dose were identified as parameters associated with decreased kidney function. Mean serum creatinine was increased from 74.6 micromol/L before treatment to 86.1 micromol/L at 1 year after chemoradiotherapy (p < 0.001). In patients with a follow-up of 18-28 months, one case of severe renovascular hypertension was observed. CONCLUSION: A progressive relative functional impairment of the left kidney in patients after postoperative chemoradiotherapy for gastric cancer is demonstrated. To optimize the survival benefit that can be established with adjuvant regimens, strategies to minimize the dose to the kidneys and other critical organs should be explored.

Limitations of the planning organ at risk volume (PRV) concept.

PURPOSE: Previously, we determined a planning target volume (PTV) margin recipe for geometrical errors in radiotherapy equal to M(T) = 2 Sigma + 0.7 sigma, with Sigma and sigma standard deviations describing systematic and random errors, respectively. In this paper, we investigated margins for organs at risk (OAR), yielding the so-called planning organ at risk volume (PRV). METHODS AND MATERIALS: For critical organs with a maximum dose (D(max)) constraint, we calculated margins such that D(max) in the PRV is equal to the motion averaged D(max) in the (moving) clinical target volume (CTV). We studied margins for the spinal cord in 10 head-and-neck cases and 10 lung cases, each with two different clinical plans. For critical organs with a dose-volume constraint, we also investigated whether a margin recipe was feasible. RESULTS: For the 20 spinal cords considered, the average margin recipe found was: M(R) = 1.6 Sigma + 0.2 sigma with variations for systematic and random errors of 1.2 Sigma to 1.8 Sigma and -0.2 sigma to 0.6 sigma, respectively. The variations were due to differences in shape and position of the dose distributions with respect to the cords. The recipe also depended significantly on the volume definition of D(max). For critical organs with a dose-volume constraint, the PRV concept appears even less useful because a margin around, e.g., the rectum changes the volume in such a manner that dose-volume constraints stop making sense. CONCLUSION: The concept of PRV for planning of radiotherapy is of limited use. Therefore, alternative ways should be developed to include geometric uncertainties of OARs in radiotherapy planning.

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.

Investigation of the added value of high-energy electrons in intensity-modulated radiotherapy: four clinical cases.

PURPOSE: Intensity-modulated radiotherapy (IMRT) with photon beams is currently pursued in many clinics. Theoretically, inclusion of intensity- and energy-modulated high-energy electron beams (15-50 MeV) offers additional possibilities to improve radiotherapy treatments of deep-seated tumors. In this study the added value of high-energy electron beams in IMRT treatments was investigated. METHODS AND MATERIALS: In a comparative treatment planning study, conventional treatment plans and various types of IMRT plans were constructed for four clinical cases (cancer of the bladder, pancreas, chordoma of the sacrum, and breast). The conventional plans were used for the actual treatment of the patients. The IMRT plans were optimized using the Orbit optimization code (Löf et al., 2000) with a radiobiologic objective function. The IMRT plans were either photon or combined electron and photon beam plans, with or without dose homogeneity constraints assuming standard or increased radiosensitivities of organs at risk. RESULTS: Large improvements in expected treatment outcome are found using IMRT plans compared to conventional plans, but differences in tumor control probability (TCP) and normal tissue complication probabilities (NTCP) values between IMRT plans with and without electrons are small. However, the use of electrons improves the dose-volume histograms for organs at risk, especially at lower dose levels (e.g., 0-40 Gy). CONCLUSIONS: This preliminary study indicates that addition of higher energy electrons to IMRT can only marginally improve treatment outcome for the selected cases. The dose-volume histograms of organs at risk show improvements for IMRT with higher energy electrons, which may reduce tumor induction but does not substantially reduce NTCP.

Geometrical uncertainties, radiotherapy planning margins, and the ICRU-62 report.

In this paper, we elaborate on the proposals in the ICRU-62 report concerning planning target volume (PTV) margins for geometrical uncertainties during radiotherapy, such as variations in patient set-up and internal organ motion. According to the ICRU, these margins should be such that the planned dose in the PTV is representative of the real dose in the 'moving' clinical target volume (CTV). We demonstrate that the dosimetrical consequences of systematic and random geometrical uncertainties are fundamentally different, which should be reflected in margin calculations. The recommendation in the ICRU-62 report, to quadratically add standard deviations for systematic (Sigma(tot)) and random (sigma(tot)) errors to determine an overall standard deviation for margin calculations, is therefore generally not valid. Instead, a previously published recipe for PTV margin calculation, M = 2Sigma(tot) + 0.7sigma(tot), does indeed account for the different impact of systematic and random errors on the dose in the CTV. If, for both random and systematic uncertainties, the internal and external errors are uncorrelated and quantified by the standard deviations sigma(int), sigma(ext), Sigma(int), Sigma(ext), then Sigma(tot) = square root (Sigma(int)(2) + Sigma(ext)(2)) and sigma(tot) = square root (sigma(int)(2) + sigma(ext)(2)). If the PTV margin thus acquired is deliberately reduced to spare normal tissues, the planned PTV dose is not representative of the CTV anymore. Therefore, we recommend to also report the minimum dose in the volume originally defined by the recipe (designated RTV, i.e. representative target volume).

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.

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.